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José Tarquínio Prisco (Titular – Cadeira: 20);

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Cadeira Acadêmico Patrono

01 José Henrique Leal Cardoso Samuel Pessoa
02 João Lucas Marques Barbosa Joaquim Gomes de Souza
04 Paulo Bonavides Jáder de Carvalho
06 Francisco Militão de Sousa Renato Braga
07 Afrânio Aragão Craveiro Hugo Lopes de Mendonça
08 Tarcisio Haroldo C. Pequeno Prisco Bezerra
09 Manassés Claudino Fonteles Lauro Solero
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21 Maria Clélia Lustosa Costa Thomaz Pompeu Sobrinho
22 Maria Zélia Rouquayrol Rodolfo Teófilo
23 Ana Cristina de Oliveira M. Moreira José Higino Ribeiro dos Santos
24 Antônio de Albuquerque Sousa Filho José Guimarães Duque
25 Geraldo de Sousa Tomé Luigi Bogliolo
27 Vicente de Paulo Pereira Barbosa Vieira Arrojado Lisboa
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30 Enéas Gomes Filho José Xavier Filho
31 José Nilson Bezerra Campos Francisco Gonçalves de Aguiar
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34 José Ferreira Nunes Silvio Barbosa Cardoso
35 Luiz Drude de Lacerda Ícaro de Sousa Moreira
36 Renato de Azevedo Moreira Expedito José de Sá Parente
37 João Cesar Moura Mota Oswaldo Evandro Carneiro
38 Andrelina Noronha Coelho de Souza Oliveira Riedel
39 Joaquim Celestino Junior José Júlio da Ponte Filho
40 Selene Maia de Morais Francisco José de Abreu Matos
41 Luiz Sérgio Gadelha Vieira Ari de Sá Cavalcante
42 Geraldo Arraes Maia Francisco A. de Andrade e Castro
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48 Arlindo de Alencar Araripe N. Moura João Ambrósio de Araujo Filho
49 Marta Maria de França Fonteles Caio Lóssio Botelho
50 Fernanda Montenegro de C. Araújo José Jarbas Studart Gurge

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Prof. Dr. Benedito Vasconcelos Mendes – Escola Superior de Agricultura de Mossoró
Profa. Dra. Dafna Scwartz - Ben-Gurion University of the Negev – Israel
Prof. Emérito Dr. Raphael Bar-El – Ben-Gurion University of the Negev – Israel
Prof. Dr. Raimundo Braz Filho - Pesquisador Visitante Emérito da FAPERJ/UFRRJ/UENF, Prof. Emérito da UFRRJ

e da UENF, Prof. Honoris causa da UFC e da UFPB, Pesquisador Sênior do CNPq,
Membro Titular da ABC
Prof. Dr. Manoel Abílio Queiroz - Professor Titular Universidade do Estado da Bahia; Prof. Visitante da Universidade

do Estado da Bahia
Prof. Dr. Melquíades Pinto Paiva - Engenheiro Agrônomo - UFC (1952); Dr. em Ciências, Instituto de Biociências da

USP (1972)

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Artigos de Revisão / Review Articles 11
18
The use of experimental animal models for the study of pulmonary hypertension
Cardoso-Teixeira, A.C., Oliveira-Abreu, K., Alves, A.V., Coelho-de-Souza, A.N. & Leal-
Cardoso, J.L.

A Rede Federal de Educação Profissional e Tecnológica no Ceará: 110 anos de trajetória
Carvalho, J.M.

Artigos Científicos / Scientific Articles 25
35
Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced diabetic mice 40
Silva, J.M.A.; Guedes, M.I.F.; Paim, R.T.T.; Silva, J.Y.G.; Rodrigues, A.L.M.; Viana, D.A. &
Morais, S.M. 48
53
Verificação da aplicação de isomalte e xilitol como substitutos do açúcar na formulação de
pirulitos 66

Pinheiro, A.R.; Oliveira, E.S. & Aquino, A.C.

Bronchodilator activity of the essential oil from Lippia sidoides in bronchial isolated from
swine Sus scrofa domesticus

Pereira-de-Morais, L.; Silva, A.A.; Silva, R.E.R.; Bastos, C.M.S.; Araújo, I.M.; Costa, R.H.S.;
Cunha, F. A.B.; Leal-Cardoso, J.H. & Barbosa, R.

The hormone melatonin, diabetes mellitus, and alterations of nervous system
Oliveira-Abreu, K.; Cardoso-Teixeira, A.C.; Coelho-de-Souza, A.N. & Leal-Cardoso, J.H.

Myracrodruon urundeuva: chemical and pharmacological evaluation from roots of the
cultivated specimens

Aquino, N.C.; Lopes, J.P.; Santos, E.S.; Vale, E.M.; Leal, L.K.A.M.; Bezerra, A.M.E.; Santos,
A.D.C.; Silveira, E.R. & Viana, G.S.B.

Hábitos alimentares: comidas reimosas e suas relações culturais
Cunha Filho, A.M.; Cavalcante, J.M.; Azevedo, F.R.C. & Mesquita, P.C.

Página

Obituários / Obtuaries 70
73
AIRTON XAVIER: das ciências exatas ao fazer literário
Silva, M.G.C.

Antônio Enéas Mendes Bezerra
Bezerra Jr., A.M.

Hino Nacional Brasileiro / Brazilian National Anthem 74
Hino do Estado do Ceará / Ceara State Anthem 75

Normas para preparo e submissão de manuscritos / Guidelines for manuscript preparation 76
and submission

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 11-17, 2020.
www.aceci.com.br

Artigo de Revisão / Review Article

The Use of Experimental Animal Models for the Study of Pulmonary
Hypertension

Ana Carolina Cardoso-Teixeira, Klausen Oliveira-Abreu, Andréa de Vasconcelos Alves,
Andrelina Noronha Coelho-de-Souza & José Henrique Leal-Cardoso

Universidade Estadual do Ceará

(Aceito para Publicação em 19/07/2020)

Author for correspondence: José Henrique Leal Cardoso, e-mail: [email protected]

Cardoso-Teixeira, A.C.; Oliveira-Abreu, K.; Alves, A.V.; Coelho-de-Souza, A.N. & Leal-Cardoso, J.L. The use of experimental
animal models for the study of pulmonary hypertension. ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 11-17, 2020.

ABSTRACT
Pulmonary hypertension (PH) is a clinical condition, with high mortality rates and characterized by several
structural and functional changes in the lungs and heart. The use of animal models, although they do not
accurately reproduce PH in human, is important for understanding its PH pathophysiology and for the search
for alternatives therapeutic for this condition. Thus, this work aimed to review the main animal models used
for the study of PH. Among the models most used for this purpose is the model induced by monocrotaline and
hypoxia.
Additional keywords: Monocrotaline; Hypoxia; SUGEN 5416.

RESUMO
Uso de modelos experimentais com animais para o estudo da hipertensão pulmonar
A hipertensão pulmonar (HP) é uma condição clínica, com altas taxas de mortalidade e caracterizada por
diversas alterações estruturais e funcionais nos pulmões e no coração. O uso de modelos animais, embora não
reproduzam fielmente a HP humana é importante para a compreensão da fisiopatologia da HP e para a busca
de alternativas terapêuticas para essa condição. Assim esse trabalho teve como objetivo fazer uma revisão sobre
os principais modelos animais utilizados para o estudo da HP. Dentre os modelos mais utilizados para essa
finalidade encontra-se o modelo induzido por monocrotalina e por hipóxia.
Palavras-chave adicionais: Monocrotalina; Hipóxia; SUGEN 5416.

INTRODUCTION Pulmonary hypertension is marked by
several changes in pulmonary circulation, a
Pulmonary hypertension (PH) is a serious and system of blood vessels with high distensibility
progressive disease with high rates of morbidity and low resistance. Pulmonary circulation
and mortality. Although some authors consider is characterized by low levels of pulmonary
it rare, studies show that its incidence has been intravascular blood pressure with normal mean
increasing. The incidence rate is approximately pulmonary arterial pressure of 14.0 ± 3.3 mmHg.
2-5 cases per million of adults, although the Several factors, such as hypoxia, can act on this
prevalence and incidence varies, depending on system leading to the development of pathologies
the type of PH. In addition, this condition is more such as PH (Suresh & Shimoda, 2016; Hewes et
prevalent in women and can affect 6% of the al., 2020).
population over 85 years. Symptoms of PH are
nonspecific, but the individual often has dyspnea Currently, PH is assessed by right heart
(respiratory distress) upon physical exercise, that catheterization and is defined as mean pulmonary
is progressive, fatigue and exhaustion (Galiè et arterial pressure at rest ≥ 25 mmHg. However,
al., 2015; Hoeper et al., 2016, 2017; Fernández et changes in the definition of this pathology
al., 2019; Jasemi et al., 2020). were suggested at the 6th World Symposium on
Pulmonary Hypertension. It was recommended

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 11

The use of experimental animal models for the study of pulmonary hypertension

that PH should be defined when mean pulmonary databases, PubMed and Scielo in the last 5 years
arterial pressure values are > 20 mmHg (Galiè et (2015 - 2020).
al., 2015; Hoeper et al., 2016, 2017; Arvanitaki et
al., 2019; Hewes et al., 2020; Rao et al., 2020). Animal Models of Pulmonary Hypertension
Several animal models are used for the study of
The first classification of PH was proposed PH. Among these the most used are the lesion
in 1973, when it was classified as primary or model induced by monocrotaline and hypoxia
secondary, according to the causal agent or risk (Kim & Choi, 2019) (Table 1).
factors. The most recent classification of PH was
carried out at the World Symposium, held in Nice Monocrotaline-induced PH (MCT) Model
(France) in 2013. It groups PH into five general Monocrotaline (MCT) is an alkaloid obtained
groups of aetiology: (1) Pulmonary arterial from the seeds of Crotalaria spectabilis. The use of
hypertension (PAH), accounts for heritable, these seeds to induce changes in the pulmonary
idiopathic, drug or HIV-related causes among vasculature has been described for more than
others; (2) PH due to left heart disease; (3) PH 50 years. To produce these lesions, MCT is
due to lung diseases and/or hypoxia (decreased oxidized in MCT pyrrole in the liver, followed
oxygen rates); (4) chronic thromboembolic PH by hematogenous transport to the lung, causing
and other pulmonary artery obstructions and; injuries to the pulmonary endothelium (Lalich &
(5) PH with unclear multifactorial mechanisms Merkow, 1961; Zhuang et al., 2018).
(Alves-Jr; Oleas & Souza, 2017; Galiè et al., 2015;
Gomes et al., 2018; Xiong et al., 2018; Fernandez et One of the first reports on the effects of
al., 2019). MCT on blood vessels was carried out by Lalich
& Merkow (1961). Female Sprague-Dawley
Pulmonary hypertension is characterized rats received crushed seeds of C. spectabilis in
by several pulmonary and/or cardiac changes. different concentrations (0.013, 0.025, 0.05, 0.01
Among the pulmonary vascular alterations is and 0, 20%). It was observed that the animals
the increase in peripheral vascular resistance, developed changes only in the cardiac and
endothelial dysfunction, hypertrophy and pulmonary vascular beds, presenting pulmonary
proliferation of muscle cells present in the arterial inflammation, pulmonary hemorrhage
pulmonary arteries and reduction of the vascular and acute myocarditis (Lalich & Merkow, 1961).
lumen. It can also be observed the increase Kay et al (1967) demonstrated that prolonged oral
in adventitious thickening of the precapillary administration of C. spectabilis seeds (0.1%) in rats
pulmonary arteries, development of lesions in the induces pulmonary hypertension associated with
form intricate network (plexiform) and increased hypertrophy of the right ventricle and an increase
vasomotor tone. Among the cardiac alterations in the medial thickness of the pulmonary trunk
can be observed: ventricular hypertrophy and and small pulmonary arteries.
right heart failure. In addition, there are reports
of altered immune, metabolic and inflammatory In addition to use by ingestion, the
processes in this pathology (Mendonça et al., 2017; administration of a single injection of subcu-
Callejo et al., 2018; Fujita et al., 2018; Humbert et taneous or intraperitoneal MCT is sufficient to
al., 2019). induce PH with pathological pulmonary and
cardiac changes similar to human PH (Pacagnelli
There is an imbalance between several et al., 2016). Zhuang et al (2018) induced a PH
physiological processes during the progression model similar to chronic PAH with two MCT
of PH and it is necessary to constantly study injections (20 mg/kg, ip). They observed an
these changes. Thus, the use of animal models increase in the percentage of survival in rats,
is important in this process. Animal models of less inflammation and less fibrosis during the
PH do not accurately reproduce PH in human, experimental period.
due to several factors such as: the time course at
which hypertension appears. However, the use of Several changes related to PH in human
experimental models is important to understand can be observed in animals with PH induced
the pathophysiology of PH as well as to perform by MCT such as tunica intima (innermost layer)
tests in search of therapies for this pathology hypertrophy and hyperplasia of vessels (Xiong et
(Gomez-Arroyo et al., 2016). al., 2018). Among the cardiac changes observed
in this experimental model are: right ventricular
Thus, the objective of this work was to hypertrophy, worsening of the right ventricular
carry out a review of experimental animal models contractile function and an increase in systolic
for the study of PH. Works were used in the

12 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Cardoso-Teixeira, A. C., et al

Table 1- Animal models of pulmonary hypertension (PH)

Group Model Animals Induction Reference
of PH MCT Wistar MCT (30mg/kg, ip, single dose) Fujita et al., 2018

I

I MCT Sprague Dawley MCT (60mg/kg, sc , single dose Xiao et al., 2017

I MCT Sprague Dawley MCT (20mg/kg, ip, double dose) Zhuang et al., 2018

I MCT/P Sprague Dawley Left pneumonectomy + MCT (60mg/kg, Yin et al., 2017
sc, single dose)

I MCT/HX Sprague Dawley MCT (40mg/kg, sc, single dose)+ Huang et al., 2015
hypobaric hypoxia

I MCT/HX Sprague Dawley MCT (60mg/kg, ip, single dose)+ Lan et al., 2015
hypobaric hypoxia

I MCT/HX Wistar MCT (60mg/kg, ip, single dose) + Coste et al., 2017
hypobaric hypoxia

I-III SU/HX Sprague Dawley Sugen 5416 (20mg/kg, sc, single dose) + Christou et al., 2018
hypobaric hypoxia

I-III SU/HX Wistar Sugen 5416 (20mg/kg, sc, single dose) + Callejo et al., 2018
hypobaric hypoxia

I-III SU/HX C57BL/6J Sugen 5416 (20mg/kg, sc triple dose) + Bueno-Beti et al., 2018
hypobaric hypoxia
Sugen 5416 (20mg/kg, sc, single dose) +
I SU/M Sprague Dawley morfin (10mg/kg, ip) Agarwal et al., 2020

II LAS Sprague Dawley Surgery Fujimoto et al., 2017

Polystyrene microspheres (iv, single
IV PE/SU Sprague Dawley dose) + SU5416 (20 mg/kg, sc, single Neto-Neves et al., 2017

dose)

MCT, monocrotaline; HX, hypoxia; SU, SUGEN 5416; M, morfin; P, pneumonectomy; ip, intraperitoneal; sc, subcutaneous

pressure in the right ventricle, the latter being types of PH (Rafikova et al., 2016; Fujita et al.,
the most prevalent characteristic (Pacagnelli et 2018; Zhuang et al., 2018; Sugawara et al., 2019).
al., 2016; Yin et al., 2016; Mendonça et al., 2017; According to Xiao et al (2017) MCT aggregates
Zhuang et al., 2018). and activates CaSR, a receptor sensitive to
extracellular calcium, from pulmonary artery
Pulmonary vascular remodeling is also one endothelial cells to trigger endothelial damage
of the characteristics of the PH model induced by and induce PH.
MCT similar to PH in human. In this model, an
increase in the total thickness of the pulmonary It has been shown that therapy with
arterioles wall, hypertrophy of smooth muscle mesenchymal stromal cells (derived from
cells presents in the middle layer of pulmonary mesenchymal embryonic connective tissue),
arteries and thickening of the tunica intima in pre- reduced pulmonary vascular remodeling in a
acinar and intra-acinar arteries can be observed model of hypertension induced by MCT. This
(Mendonça et al., 2017; Sharma et al., 2018; Fujita reduction was due to the reduction of histological
et al., 2018; Zhuang et al., 2018). Furthermore, it damage, thickening of smooth muscle cells,
was observed that in mice, there is damage to macrophage density, increased proapoptotic
pulmonary vascular endothelial cells and these mediators in lung tissue and decreased markers
induce pulmonary vascular remodeling through of cell proliferation in the pulmonary artery
bone mediated endothelial progenitor cells (Mendonça et al., 2017).
(Aliotta et al., 2017; Sugawara et al., 2019).
Increased oxidative stress and the production
According to several authors, MCT induces of reactive oxygen species, characteristic of PH in
an intense inflammatory reaction in pulmonary human, are also present in MCT animal model.
arteries and arterioles, endothelial damage and It was observed, the participation of NADPH
hyperplasia of the pulmonary interstitium, which oxidase (Nox), xanthine oxidase (XO), superoxide
is the genesis of the development of several dismutase (SOD) and decoupled endothelial NO

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 13

The use of experimental animal models for the study of pulmonary hypertension

synthase (eNOS) (Steven et al., 2017; Fujita et al., addition, a reduction in the right ventricular
2018). Steven et al (2017) demonstrated that MCT ejection fraction has been demonstrated after 4
induced oxidative stress in the vascular wall, weeks of experimentation (Lan et al., 2015; Coste
heart and blood of rats. They observed increased et al., 2017; Zhang et al., 2018).
levels of expression of pulmonary endothelin
mRNA (ET-1), ET-1 converting enzyme and ET-1 The MCT/HX also shows several structural
receptors. Sharma et al. (2018), demonstrated and functional changes in the pulmonary
that animals with PH induced by MCT showed vasculature. This model shows increased
neuroinflammation, with activation of microglial vascular reactivity in intrapulmonary arteries and
cells and increased mRNA for pro-inflammatory remodeling with plexiform lesions, pulmonary
cytokines (IL-1β, IL-6 and TNF-α). In addition, arterial medial thickening (Coste et al., 2017; Zhang
increased sympathetic impulse and plasma et al., 2018). In addition, neo-intima occlusion (a
norepinephrine were observed. layer of tissue formed in response to damage to
the blood vessel’s inner layer) demonstrates that
Among the disadvantages presented by this model is more severe than the MCT model
this model is the systemic toxicity of MCT and or hypoxia alone (Lan et al., 2015). Huang et al
the absence of plexiform lung lesions, making (2015) demonstrated that the formation of neo-
this model not faithfully reproduce PH in human intima may be related to increased expression of
(Xiong et al., 2018). caveolin-1 in smooth muscle cells.

PH Model Induced by Monocrotaline and Elevated levels of TNF-α, IL-6 and
Pneumonectomy (MCT/P) interleukin-1β are also observed, indicating a
Tanakaetal (1996),usingthemonocrotalinemodel, chronic inflammatory process in this PH model
demonstrated that high pressure is not a sufficient (Coste et al., 2017; Zhang et al., 2018).
stimulus to remodel the elastic pulmonary
artery. They concluded that the type of injury PH Model Induced by SUGEN 5416 and Chronic
and the associated hemodynamic conditions are Hypoxia (SU/HX)
necessary conditions for pulmonary vascular SU/HX is a model of severe pulmonary
remodeling. Okada et al (1997) established a new hypertension associated with pre-capillary
model of PH when administering MCT, before or arterial occlusion and plexiform arteriopathy.
after pneumonectomy (surgical partial removal It is performed by hypoxia associated with an
of a lung). injection of SUGEN 5416, an inhibitor of vascular
endothelial growth factor (VEGF), important for
Among the cardiac changes in this PH endothelial cell homeostasis. Rats treated with
model is right ventricular hypertrophy, which SUGEN 5416 in a normoxic situation developed
is greater than the hypertrophy observed in the mild PH while animals under hypoxia developed
model only with the administration of MCT severe PH associated with pre-capillary arterial
(Okada et al., 1997; Yin et al., 2017; Zhao et al., endothelial cell proliferation (Taraseviciene-
2019). Stewart et al., 2001).

The MCT/P model reproduces the main Animals with SU/HX present an increase in
aspects of human pathology with neo-intimal mean, systolic and diastolic pulmonary pressure
formation, smooth muscle hypertrophy and associated with various cardiac, metabolic and
proliferative lesions (Yin et al., 2016; Okada et al., vascular changes. It can be observed that SU/HX
1997; Lachant et al., 2018; Zhao et al., 2019). leads to an increase in heart rate, right ventricular
hypertrophy and a reduction in body mass
PH Model Induced by Monocrotaline and (Callejo et al., 2018; Jayasekera et al., 2020).
Chronic Hypoxia (MCT/HX)
Lan et al. (2015) and Coste et al. (2017) demonstrated SU/HX leads to the development of
that the combination of MCT injection (60mg/kg, vascular changes of structural and functional
i.p.) with exposure to chronic hypoxia (3-4 weeks) character. An intense vascular remodeling can be
develops PH in Wistar and Sprague-Dawley rats, observed with an increase in the thickness of the
respectively. pulmonary arteries compared to normotensive
animals, hypertrophy of smooth muscle cells
In this PH model, an increase in pulmonary in the middle layer of pulmonary arteries of
arterial pressure associated with an increase resistance. Additionally, a decrease in the
in right ventricular systolic pressure and right contractile response of the pulmonary arteries
ventricular hypertrophy can be observed. In is reported both in electromechanical and

14 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Cardoso-Teixeira, A. C., et al

pharmacomechanical coupling and decreased of the right ventricle in response to exercise,
relaxation of the pulmonary artery with reduced severe peripheral edema, respiratory distress,
responsiveness to the NO-cGMP relaxation hepatomegaly and ascites. In addition, intense
pathway (Callejo et al., 2018; Christou et al., 2018). vascular remodeling was observed with medial
hypertrophy in small arteries, proliferation of
Among the disadvantages of this model is intima with lumen obliteration and increased
the unreliable development of right ventricular inflammatory processes (Neto-Neves et al., 2017).
failure (Xiong et al., 2018).

PH Model Induced by SUGEN 5416 and FINAL CONSIDERATIONS
Morphine (SU/M)
Agarwal et al (2020) demonstrated that SUGEN Animal models for testing PH induced by
5416 associated with an intraperitoneal injection drugs such as monocrotaline or SUGEN 5416,
of morphine leads to the development of associated with other strategies, develop
pulmonary arterial hypertension with high structural and functional changes similar to
systolic pressure in the right ventricle associated human PH. Animal models of PH, although they
with ventricular hypertrophy with an increase in do not faithfully reproduce the changes present
the size of cardiomyocytes. Additionally, collagen in PH in human, are a good study strategy for the
deposition and increased fibrosis were observed. pathophysiological changes of PH. In addition,
these models are useful in the development of
The vascular remodeling observed in the therapies for the treatment of PH.
SU/M model is marked by hypertrophy of the
smooth muscle layer in the pre-acinar and intra- References
acinar pulmonary arteries. It can also be observed
neo-intima thickening of the vessels, stimulating Agarwal, S., Harter, Z.J.; Krishnamachary, B.; Chen,
the proliferation of endothelial cells (Agarwal et L.; Nguyen, T.; Voelkel, N.F. & Dhillon, N. K. Sugen-
al., 2020). morphine model of pulmonary arterial hypertension.
Pulmonary circulation, v. 10, n. 1, 2020.
PH Model Associated to Left Atrial Stenosis
(LAS) Aliotta J.M.; Pereira, M.; Wen, S.; Dooner, M.S.; Del
The model of stenosis of the left atrium aims to Tatto, M.; Papa, E.; Cheng, Y.; Goldberg, L.; Ventetuolo,
reproduce the pathophysiological changes of the C.E.; Liang, O.; Klinger, J.R. & Quesenberry, P.J. Bone
PH 2 group. PH induction occurs with a surgical marrow endothelial progenitor cells are the cellular
procedure where an interruption suture is mediators of pulmonary hypertension in the murine
performed in the left atrium. The animals develop monocrotaline injury model. Stem cells translational
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pleural effusion, increased pressure in the right
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(Fujimoto et al., 2017; Xiong et al., 2018).
Arvanitaki, A.; Boutsikou, M.; Anthi, A.;
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Neto-Neves et al (2017) demonstrated an animal G.; Karvounis, H.; Karyofyllis, P.; Mitrouska,
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thromboembolic pulmonary hypertension. Panagiotidou, E.; Pitsiou, G.; Rammos, S.; Stagaki, E.
Sprague-Dawley rats received a single dose of & Stanopoulos, I. Hellenic Society for the Study of
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ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 18-24, 2020.
www.aceci.com.br

Artigo de Revisão / Review Article

A Rede Federal de Educação Profissional e Tecnológica
no Ceará: 110 Anos de Trajetória

Joelia Marques de Carvalho

Doutora em Ciência e Tecnologia (UFC), Especialista em educação profissional e tecnológica (IFCE),
Eng. Alimentos (UFC); Instituto Federal de Educação Ciência e Tecnologia – Campus Caucaia,
Rua Francisco da Rocha Martins s/n, Pabussu, Caucaia-Ce, CEP 61609-090

(Aceito para Publicação em 30/07/2020)

Autor para correspondência: Joelia Marques de Carvalho, e-mail: [email protected]

Carvalho, J.M. A Rede Federal de Educação Profissional e Tecnológica no Ceará: 110 anos de trajetória. ANAIS da Academia
Cearense de Ciências, v. 4, n. 1, p. 18-24, 2020.

RESUMO
Em dezembro de 2019, a Rede Federal de Educação Profissional e Tecnológica (RFEPT) completa 110 anos de
criação. Iniciando suas atividades em 1909, por decreto do então presidente Nilo Peçanha, foi criada na forma
de Escola de Aprendizes Artífices, como foco na formação para o trabalho. Ao longo destes anos, manteve sua
característica de formação técnica de qualidade, sendo uma das referências neste tipo de formação no Brasil.
Cresceu na sua estrutura, passando a denominar-se Liceu Industrial, Escola Industrial do Ceará, Escola Técnica
Federal do Ceará. Contudo, também agregou durante o tempo, a necessidade de ampliar seus horizontes,
integrando muito mais que o ensino técnico, mas também desenvolvendo tecnologia. Em 1998 passou a atuar
na formação de cursos superiores de tecnologia, no formato dos Centros Federais de Educação Tecnológica
(CEFET). A partir da constituição dos Institutos Federais de Educação, Ciência e Tecnologia em 2008, se firmou
como Instituto Federal de Educação, Ciência e Tecnologia do Ceará, que hoje abrange a formação desde o ensino
médio profissionalizante à pós-graduação strictu sensu. Com essa trajetória, a RFEPT se recria em sua capacidade
de formar recursos humanos, não só para o mercado de trabalho, mas também para o desenvolvimento humano
em sua completude, integrando ciência, tecnologia, arte e cultura, se renovando.

Palavras-chave adicionais: Ciência;Tecnologia; Educação; CEFET; RFEPT.

ABSTRACT
The Federal Network of Professional and Technological Education in Ceará: 110 Years of Trajectory
In December 2019, the Federal Network of Professional and Technological Education complete 110 years of
creation. Beginning its activities in 1909, by then-president Nilo Peçanha, it was created in the form of School of
Apprentice Craftsmen, with a focus on training for work. Over the years, it has maintained its characteristic of
quality technical training, which is one of the references in this type of training in Brazil. It grew in its structure,
changing its name to Liceu Industrial, Escola Industrial do Ceará, Escola Técnica Federal do Ceará. However, it
also added over time, the need to broaden its horizons, integrating much more than technical education, but also
developing technology. In 1998 it started to work on the formation of higher technology courses, in the format of
the Federal Technological Education Centers (CEFET). Since the creation of the Federal Institutes of Education,
Science, and Technology in 2008, it has established itself as the Federal Institute of Education, Science, and
Technology of Ceará, which today covers training from professional high school to post-graduation. With this
trajectory, it was renewed in its capacity to train human resources, not only for the job, but also for human
development in its entirety, integrating science, technology, art, and culture.
Additional keywords: Science; Technology; Education; CEFET; RFEPT.

INTRODUÇÃO profissionalizante, a Rede Federal, que engloba
os Institutos Federais de Educação, Ciência e
No ano de 2019, a Rede Federal de Educação Tecnologia, também congrega os Centros Federais
Profissional e Tecnológica (RFEPT) chegou de Educação, às Escolas Técnicas vinculadas
aos 110 anos. Muito mais que uma escola às Universidades Federais, a Universidade

18 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Carvalho, J.M.

Tecnológica Federal do Paraná e o Colégio Pedro Figura 1- Primeira e segunda sede da Escola de
II. Aprendizes Artífices do Ceará. Fonte: Memorial do

Essa trajetória teve início em 1909, quando o IFCE, (2020).
então presidente Nilo Peçanha assinou o Decreto
nº 7.566, criando 19 “Escolas de Aprendizes
Artífices”. Foi o passo inicial de um percurso
duradouro e reconhecido na formação técnica
profissionalizante no Brasil.

Até assumir a configuração atual, a RFEPT
se modernizou, e atualmente integra além
dos tradicionais cursos técnicos de formação
profissional, uma estrutura inovadora, que
permite o estudante partir de uma formação
em nível médio até um doutorado na mesma
instituição. O desenho atual da estrutura da Rede
Federal foi concebido em 2008, com a Lei 11.892.
Por meio deste desenho, a formação deixa de ser
somente técnica, para ser tecnológica.

O objetivo desta Revisão é apresentar um
breve relato, das ações de desenvolvimento
científico da RFEPT, em especial no Ceará,
através da trajetória do Instituto Federal do Ceará
(IFCE) em alusão aos 110 anos comemorados em
dezembro de 2019.

INÍCIODA REDE FEDERAL DE EDUCAÇÃO
PROFISSIONAL E TECNOLÓGICA NO
CEARÁ

Segundo Candido et al. (2019) em meados de 1910, Figura 2- Terceira e quarta sede da Escola de
embora funcionassem em instalações inapro- Aprendizes Artífices do Ceará. Fonte: Memorial do
priadas e com recursos limitados, estavam em IFCE (2020).
atividade as 19 Escolas de Aprendizes Artífices
propostas no Decreto 7566/09, inclusive a do A sede que ocuparia o atual Campus
Ceará, que foi inaugurada em 24 de maio de 1910. Fortaleza, foi planejada pelo então diretor Waldir
Diogo de Siqueira, que contratou a empresa
O início das atividades no Ceará, não construtora do arquiteto húngaro Emílio Hinko.
foi onde atualmente funciona o IFCE Campus O projeto, com influência neoclássica, caracteriza-
Fortaleza, mas passou por diversos locais até se pela simetria (Memorial, 2020). Nessa sede,
conseguir seu espaço definitivo de instalação. De funcionaram as denominações Escola Industrial
acordo com a pesquisa realizada por Candido do Ceará, Escola Técnica Federal do Ceará (ETFCE)
et al. (2019), em virtude do desenvolvimento da e Centro Federal de Educação Tecnológica do
Instituição e do crescente número de alunos,
surgiu a necessidade de um prédio mais amplo,
que melhor se adequasse às necessidades
pedagógicas de uma instituição escolar daquele
porte.Apenas em 1952, a Instituição ocuparia um
prédio próprio, construído em terreno situado na
Avenida Treze de Maio, fruto de uma doação do
Estado do Ceará à União Federal, realizada em 17
de janeiro de 1940.

As Figuras ilustrativas (1, 2, 3, 4, 5, 6)
apresentam as diversas sedes onde a Escolas de
Aprendizes Artífices funcionou até sua instalação
definitiva (atual Campus Fortaleza).

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 19

A Rede Federal de Educação Profissional e Tecnológica no Ceará

Figura 3- Quinta sede do agora então Liceu Industrial Figura 5- Reitoria do Instituto Federal do Ceará
do Ceará, denominação a partir de 1940. Fonte: (IFCE). Fonte: Comunicação IFCE (2020).

Memorial do IFCE (2020).

Ceará (CEFET-CE). A Figura 4 mostra a vista INTERIORIZAÇÃO DA REDE FEDERAL
aérea da edificação situada na Avenida 13 de DE EDUCAÇÃO PROFISSIONAL E
maio, bairro Benfica em Fortaleza. Ao fundo da TECNOLÓGICA
foto é possível ver o Estádio Presidente Vargas.
A interiorização da educação profissional e
Figura 4- Vista aérea do prédio definitivo da Rede tecnológica no Ceará surgiu muito antes do
Federal de Educação Profissional e Tecnológica processo de expansão promovido pela Lei
(RFEPT) em Fortaleza, atual Instituto Federal do 11.892/2008. Na verdade, essa lei serviu como
Ceará (IFCE), Campus Fortaleza. Fonte: Memorial do base para a unificação institucional da rede
IFCE (2020). federal. Este processo aconteceu no Ceará com a
incorporação dos Centros Federais de Educação
Atualmente em Fortaleza, além do prédio Tecnológica (CEFET) e das Escolas Agrotécnicas
clássico da Av. 13 de Maio, o prédio da antiga Federais.
Delegacia do Ministério da Educação, situado na
Av. Nogueira Acioly abriga o Polo de Inovação No município do Crato, a história do IFCE
do IFCE e mais recentemente, foi construída a começou em 1954, com a criação de uma Escola
sede da Reitoria do IFCE. Segundo informações Agrotécnica no município, voltada para o ensino
do Memorial do IFCE (2020) o terreno onde se agropecuário. O primeiro curso foi o de Tratorista,
instalou a Reitoria do Instituto Federal do Ceará em 1955. Quase dez anos depois, em fevereiro
foi doado pelo Ministério da Agricultura, em de 1964, o espaço mudou de nome e passou a se
22 de outubro de 2010, situado na Rua Jorge chamar Colégio Agrícola do Crato, e, em 1979,
Dummar, nº 1.703, Jardim América, adquirido virou Escola Agrotécnica Federal de Crato. O
por doação do Município de Fortaleza – Ceará. A campus Iguatu do Instituto Federal de Educação,
Figura 5 mostra a sede da Reitoria do IFCE. Ciência e Tecnologia do Ceará teve origem em
1955, com a criação do curso de extensão de
Economia Rural Doméstica, ainda vinculado ao
Ministério da Agricultura. Em 1962, o Ministério
da Agricultura criou o Colégio de Economia
Doméstica Rural, Elza Barreto. Com a função de
formar professores para o magistério do curso
de Extensão em Economia. Em 4 de setembro de
1979, mudou o nome para Escola Agrotécnica
Federal de Iguatu. A instituição manteve essa
denominação até dezembro de 2008, quando foi
incorporada à estrutura do IFCE.

O CEFET-CE inaugurou duas Unidades de
Ensino Descentralizadas (UnEDs) nas cidades
de Cedro e de Juazeiro do Norte. A Unidade de

20 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Carvalho, J.M.

Ensino Descentralizada de Juazeiro do Norte-CE Federais (Aguiar & Pacheco, 2017).
começou a funcionar somente em 11 de setembro A criação dos Institutos Federais teve como
de 1995, já a unidade do Cedro entrou em
funcionamento em 11 de setembro 1995. princípio estimular, não só a formação técnica,
mas a formação humana em sua plenitude. Com
Em 2006 foi criada a unidade de Maracanaú, nível de capilaridade nos municípios cearenses
que rapidamente foi incorporada a estrutura do muito maiores, que as Universidades, a criação
IFCE. Atualmente o IFCE conta com 35 unidades, dos Institutos Federais promoveu também a
distribuídas em todas as regiões do Ceará (Figura ciência e o desenvolvimento tecnológico no
6). interior do Estado do Ceará. Desta forma, é
precípua sua atuação na formação de recursos
É importante destacar, que com a incorporação humanos qualificados voltados também para o
de diversas unidades, os cursos ofertados também desenvolvimento científico cearense.
foram diversificados. Antes da junção das unidades, era
nítida a distinção, com as unidades do interior do Ceará, A Lei 11.892/2008, conhecida como Lei
voltadas a produção agropecuária, e a capital, com de Criação dos Institutos Federais, traz como
o desenvolvimento de áreas ditas mais tecnológicas. finalidades e objetivos destas instituições (Brasil,
Com a criação do Instituto Federal, tanto foi possível 2008):
a expansão de áreas tecnológicas no interior, como V - Constituir-se em Centro de Excelência na
também se fortaleceu as áreas vinculadas às Ciências
Agrárias, destacando-se Agronomia, Tecnologia oferta do ensino de ciências, em geral,
de Alimentos e Zootecnia. e de ciências aplicadas, em particular,
estimulando o desenvolvimento de espírito
A REDE FEDERAL E O FAZER CIENTÍFICO crítico, voltado à investigação empírica;
VI - Qualificar-se como Centro de Referência no
As atividades de pesquisa e extensão, por mais apoio à oferta do ensino de ciências nas
relevantes que possam parecer se não atualizadas instituições públicas de ensino, oferecendo
e repensadas crítica e permanentemente, tendo capacitação técnica e atualização pedagógica
em vista a democratização do saber, ao invés aos docentes das redes públicas de ensino;
de transformadoras, podem transformar-se em VII - Desenvolver programas de extensão e de
algo alienante e absolutamente desmotivador, divulgação científica e tecnológica;
deixando então de cumprir seu principal papel VIII - Realizar e estimular a pesquisa aplicada,
social: fornecer elementos para a formação de a produção cultural, o empreendedorismo,
indivíduos livres, através da construção e da o cooperativismo e o desenvolvimento
socialização do conhecimento e compromisso científico e tecnológico.
intrínseco dos objetivos gerais dos Institutos A pesquisa nos Institutos Federais torna-se
extensiva quando se dispõe a despertar o cidadão

Figura 6- Distribuição geográfica atual da rede federal no Ceará. Fonte: IFCE (2020). 21

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

A Rede Federal de Educação Profissional e Tecnológica no Ceará

para o conhecimento e seus aspectos sociais, à formação de profissionais para os diferentes
conscientizar a população sobre a importância da setores da economia e áreas do conhecimento;
ciência e da tecnologia para uma melhor qualidade d) Cursos de pós-graduação lato sensu de
de vida e estimular a percepção de que a ciência aperfeiçoamento e especialização, visando à
e a tecnologia são atividades humanas acessíveis formação de especialistas nas diferentes áreas
a todos e estreitamente ligadas aos processos do conhecimento; e
sociais. Ela se dispõe, ainda, a contribuir para e) Cursos de pós-graduação stricto sensu de
uma educação que articule as redes escolares mestrado e doutorado, que contribuam para
com os setores produtivos e a despertar vocações promover o estabelecimento de bases sólidas
democratizando o saber acumulado e produzido em educação, ciência e tecnologia, com vistas
nas diversas instituições de pesquisa e ensino no processo de geração e inovação tecnológica.
(Aguiar & Pacheco, 2017).
Segundo Pacheco (2010), os Institutos
No que tange os níveis de formação, Federais fundamentam-se na verticalização do
a Lei 11.892/2008, as possibilidades de ensino, onde os docentes atuam nos diferentes
atuação vão desde o nível médio integrado ao níveis do ensino com os discentes compartilhando
profissionalizante, até a pós-graduação strictu os espaços pedagógicos, incluindo os laboratórios
sensu (Brasil, 2008): e procurando estabelecer itinerários formativos
I - Ministrar educação profissional técnica de do curso técnico ao doutorado. Com uma
estrutura multicampi e uma territorialidade
nível médio, prioritariamente na forma de definida os Institutos Federais assumem um
cursos integrados, para os concluintes do compromisso de intervenção em suas respectivas
ensino fundamental e para o público da regiões, identificando problemas e criando
educação de jovens e adultos; soluções tecnológicas para o desenvolvimento
II-Ministrarcursosdeformaçãoinicialecontinuada sustentável, com inclusão social.
de trabalhadores, objetivando a capacitação,
o aperfeiçoamento, a especialização e a A partir da configuração como Instituto
atualização de profissionais, em todos Federal, o IFCE nos últimos dez anos aprovou 11
os níveis de escolaridade, nas áreas da cursos de Mestrado, sendo dois deles no interior
educação profissional e tecnológica; do Estado, nas cidades de Limoeiro do Norte
III - Realizar pesquisas aplicadas, estimulando (Tecnologia de Alimentos) e Sobral (Ensino de
o desenvolvimento de soluções técnicas e Física). Recentemente, foi aprovado o primeiro
tecnológicas, estendendo seus benefícios à Doutorado da instituição: o doutorado da Rede
comunidade; Nordeste de Ensino (Renoen).
IV - Desenvolver atividades de extensão de
acordo com os princípios e finalidades Pereira & Rôças (2017) destacam os
da educação profissional e tecnológica, cursos de pós-graduação em suas diferentes
em articulação com o mundo do trabalho modalidades (profissional e acadêmico) e níveis
e os segmentos sociais, e com ênfase na (aperfeiçoamento, especialização, mestrado e
produção, desenvolvimento e difusão de doutorado) não só estão previstos na legislação,
conhecimentos científicos e tecnológicos; como representam dois dos cinco nichos
V – Estimular e apoiar processos educativos que destacados para o ensino superior dentro de
levem à geração de trabalho e renda e à um IF (além de cursos superiores de tecnologia,
emancipação do cidadão na perspectiva do licenciaturas e bacharelados).
desenvolvimento socioeconômico local e
regional; e Sobre a possibilidade de atuação nos
VI - Ministrar em nível de educação superior: diversos níveis e modalidades educacionais
a) Cursos superiores de tecnologia visando à Pacheco (2010) afirma:
formação de profissionais para os diferentes
setores da economia; “A vinculação estreita entre as ciências e a
b) Cursos de licenciatura, bem como programas tecnologia, em diversas áreas, é capaz de gerar
especiais de formação pedagógica, com vistas uma concepção da formação que se configure
na formação de professores para a educação num programa ou ciclo inicial, tendo como base
básica, sobretudo nas áreas de ciências e cada uma das áreas das ciências, configuração
matemática, e para a educação profissional; que pode trazer caráter de terminalidade, como
c) Cursos de bacharelado e engenharia, visando bacharelado. A partir de então, seria possível
ao aluno o encaminhamento para os cursos
de licenciaturas (Biologia, Física, Matemática,

22 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Carvalho, J.M.

Química e afins), ou para os cursos de tecnologia, de obra profissionalizante, evoluiu para uma
ou ainda para as engenharias, etapa em que se estrutura que acompanhou a modernização do
dá a produção de conhecimento mais específico país ao longo dos anos.
em determinada área. Por sua vez, esse segundo
momento estaria estabelecendo um elo mais Sua vertente técnica, que exerceu e ainda
estreito com os cursos de pós-graduação lato e exerce com maestria, forma não só para o
stricto sensu, como forma imediata e subsequente mercado de trabalho, mas para a formação plena
para a formação. Vale ressaltar que esse modelo e humana, de um cidadão pensante e que amplia
seria capaz de desfazer barreiras criadas em relação suas possibilidades na Instituição.
aos cursos superiores de tecnologia quando da
sua vinculação à mera aplicação técnico-científica Já na perspectiva da geração de
do conhecimento, em detrimento da ciência.” conhecimento científico e tecnológico, o Instituto
Federal se destaca pela interação ativa entre
Outro ponto importante na atuação do professores e alunos, que atuam em diversos
IFCE é sua interação com o setor empresarial e níveis de formação, que possibilitam a interação
industrial no desenvolvimento de tecnologias e entre gerações de conhecimentos que se
inovação. Um ambiente específico para esta ação desenvolvem.
é o Pólo de Inovação. Em 2013, iniciou-se um
conjunto de ações que resultou na aprovação, No Ceará, bem como em outros estados
através da chamada pública 02/2014, da da federação, a presença dos Institutos Federais
implantação do Pólo de Inovação Fortaleza, para é uma marca do ensino de qualidade, que
atuar nas áreas de competência de Mobilidade possibilitam a formação de profissionais
Digital e Sistemas Embarcados. capacitados e reconhecidos por suas habilidades
e conhecimento.
As iniciativas de pesquisa aplicada,
de extensão tecnológica e de suporte ao A pesquisa científica é a base de todo o
empreendedorismo inovador, todas em apoio à conhecimento gerado na instituição, e grande
inovação, apresentam-se de diferentes maneiras tem se consolidado nos últimos 10 anos, com a
dentro das instituições da Rede Federal. criação da estrutura que conhecemos atualmente.
Além dos projetos de pesquisa e extensão já Desta forma, a verticalização do ensino, desde o
consolidados, viabilizados por programas de ensino médio, até a pós-graduação strictu senso
iniciação científica e tecnológica (PIBIC, PIBITI é uma porta aberta para o desenvolvimento de
e PIBEX) e por agências de fomento municipais, projetos, que estimulam o desenvolvimento
estaduais e federais, há também iniciativas de PD científico e tecnológico do nosso estado Ceará e
& I, realizadas por meio de acordos com entes dos de todo Brasil.
setores público e privado. Nos projetos focados
em pesquisa aplicada, a Rede Federal conta com REFERÊNCIAS
o suporte de Núcleos de Inovação Tecnológica
(NITs), e de programas de estímulo ao a criação Aguiar, L.E.V. & Pacheco, M.E. Os Institutos Federais
de negócios (Sacconi et al., 2016). de Educação, Ciência e Tecnologia como política
pública. In: Anjos, M.B.&Rôças, G. As políticas
Destacam-se nessas iniciativas de integração públicas e o papel social dos Institutos Federais de
pesquisa-sociedade as incubadoras de empresas, Educação, Ciência e Tecnologia. Natal: Editora IFRN/
complementados por empresas juniores e Parceria Editorial. 2017.
vivências empreendedoras oportunizadas por
entes parceiros. No Ceará, uma estrutura única é Brasil. Lei nº 11.892, de 29 de dezembro de 2008.
o Hotel Escola em Guaramiranga, uma estrutura Institui a Rede Federal de Educação Profissional,
do IFCE voltada para a formação na área de Científica e Tecnológica, cria os Institutos Federais
turismo, mas com o suporte de hotel e realização de Educação, Ciência e Tecnologia, e dá outras
de eventos. providências. Disponível em: http://www.planalto.
gov.br/ccivil_03/_Ato 2007-2010/2008/Lei/L11892.
CONSIDERAÇÕES FINAIS htm#:~:text=LEI%20N%C2%BA%2011.892%2C%20
DE%2029%20DE%20DEZEMBRO%20DE%20
A Rede Federal de Educação Profissional e 2008.&text=Institui%20a%20Rede%20Federal%20
Tecnológica avança em sua caminhada ao longo de,Tecnologia%2C%20e%20d%C3%A1%20outras%20
dos 110 anos comemorados em 2019. Criada em provid%C3%AAncias. Acesso: 21 jul 2020
1909 para ser uma escola de formação de mão
Candido, F.G.; Jucá, S.C.S.; Silva, S.A. & Alves,
F.R.V. Educação para o trabalho: a Escola de
Aprendizes Artífices do Ceará. Revista do
Centro de Educação UFSM. v. 44, p. 1-22. 2019.

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 23

A Rede Federal de Educação Profissional e Tecnológica no Ceará

DOI: http://dx.doi.org/10.5902/1984644434813 As políticas públicas e o papel social dos Institutos
Federais de Educação, Ciência e Tecnologia. Natal:
Comunicação IFCE. Disponível em: https://www. Editora IFRN/Parceria Editorial. 2017.

flickr.com/photos/reitoriaifce/28406630474/in/ Sacconi, E.J.C.; Lira, M.G.C.; Leão, P.H.A. & Oliveira,
R.C. Manual de Parcerias: Mecanismos e Instrumentos
album-2157672446818896/ Acesso em: 21 jul 2020 para a Dinamização de Habitats e Ecossistemas de
Empreendedorismo e Inovação na RFEPCT. 2ª edição.
Memorial do IFCE. Disponível em: https://ifce.edu. Brasília: Ministério da Educação. 2016. Disponível em:
br/memorial/memorial-do-ifce Acesso: 21 jul 2020 http://portal.mec.gov.br/index.php?option=com_
docman&view=download&alias=39661-manual-
Pacheco, E.M. Os Institutos Federais: uma revolução parcerias-dinamizacao-habitats-eco-inovacao-rfepct-
na educação profissional e tecnológica. Natal: Editora pdf&Itemid=30192 Acesso em: 21 jul 2020
IFRN. 2010.

Pereira, M.V. & Rôças, G. O ensino de pós-graduação
nos Institutos Federais. In: Anjos, M.B.& Rôças, G.

24 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 25-34, 2020.
www.aceci.com.br

Artigo Científico/ Scientific Article

Antidiabetic Effect of Fruit Juice of Spondias dulcis in Alloxan
Induced Diabetic Mice

Este trabalho é dedicado ao Prof. Dr. Melquiades Pinto Paiva pela
passagem do seu 90º aniversário e, também, porque ele deu a informação do

uso da cajarana para baixar a diabetes

Jânia Maria Augusta da Silvaa, Maria Izabel Florindo Guedesa,b, Raquel Teixeira Terceiro Paima,
José Ytalo Gomes da Silvaa, Ana Livya Moreira Rodriguesa,c, Daniel de Araújo Vianad &
Selene Maia de Moraisa,c*

a Postgraduate Program in Biotechnology, State University of Ceará, Itaperi Campus, CEP 60740-903,
Fortaleza, Ceará, Brazil; b Laboratory of Biotechnology and Molecular Biology - LBBM, State University of
Ceará, Campus Itaperi, CEP 60740-903, Fortaleza, Ceará, Brazil; c Chemistry Laboratory of Natural Products

(CLNP) Chemistry Course, State University of Ceará, Itaperi Campus, CEP 60740-903, Fortaleza, Ceará,
Brazil; d Laboratory of Pathological Anatomy and Veterinary Clinical Pathology LTDA - Pathovet, Av. dos

Expedicionários, nº 5400 - Montese, CEP 60410-234, Fortaleza, Ceará, Brazil.

(Aceito para publicação em 07/07/2020)

Author for correspondence: Selene Maia de Morais, e-mail: [email protected]

Silva, J.M.A.; Guedes, M.I.F.; Paim, R.T.T.; Silva, J.Y.G.; Rodrigues, A.L.M.; Viana, D.A. & Morais, S.M.
Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced diabetic mice. ANAIS Academia Cearense
de Ciências, v. 4, n. 1, p. 25-34. 2020.

ABSTRACT

The fruit of Spondias dulcis (Cajarana) is consumed by the local population to control diabetes. The aim of this
study was to evaluate the hypoglycemic activity of S. dulcis juice in induced diabetic mice and to identify
possible responsible constituents. The fruit juice was obtained by a mechanical pressing process. The main
components were characterized by spectrophotometry and high-performance liquid chromatography (HPLC-
DAD) and antioxidant tests. Diabetes in mice was induced by alloxane and the animals were followed for 14
days with analysis of the glycemic level and biochemical parameters of the liver and pancreas tissues at the end
of the experiment. Chemical analysis indicates the presence of condensed tannins, catechins, flavones, flavonols,
xanthones and saponins. The totals of phenols and flavonoids were 47.86 ± 0.44 mg of EAG/g and 9.53 ± 0.04 mg
of EQ/g of extract, respectively. The antioxidant activity showed a moderate result and the analysis by HPLC-
DAD revealed the presence of chlorogenic acid, rutin and quercetin. The S. dulcis aqueous extract of was able to
reduce the glycemia of diabetic animals in a percentage similar to the standard drug metformin. The animal's
tissues showed no significant changes. The improvement in glycemia in diabetic animals with the use of S. dulcis
juice may be partly related to phenolic constituents such as rutin, quercetin and chlorogenic acid, which have
hypoglycemic activity.

Additional keywords: Poliphenols; Antioxidant; Chromatography; Diabetes mellitus.

RESUMO

Efeito Antidiabético do Suco de Spondias dulcis em Alloxan Camondongos com Diabetes induzida

O fruto de Spondias dulcis (Cajarana) é consumido pela população local para controlar o diabetes. O objetivo
deste estudo foi valiar a atividade hipoglicêmica do suco de S. dulcis em camundongas diabéticas induzidas
e identificação de possíveis constituintes responsáveis. Para tanto, o extrato do fruto foi obtido por processo
de prensagem mecânica. Foi realizada a caracterização dos principais constituintes por espectrofotometria e
cromatografia líquida de alta eficiência (HPLC-DAD) e ensaios antioxidantes. O diabetes em camundongos
foi induzido por aloxano e os animais foram acompanhados por 14 dias com análise do nível glicêmico e
dos parâmetros bioquímicos dos tecidos hepáticos e do pâncreas ao final do experimento. A análise química
indica a presença de taninos condensados, catequinas, flavonas, flavonóis, xantonas e saponinas. O total de
fenóis e flavonóides foi de 47,86 ± 0,44 mg de EAG/g e 9,53 ± 0,04 mg de EQ/g de extrato, respectivamente.
A atividade antioxidante apresentou resultado moderado e a análise por HPLC-DAD revelou a presença de
ácido clorogênico, rutina e quercetina. O extrato aquoso de S. dulcis foi capaz de reduzir a glicemia de animais
diabéticos em percentual similar a droga padrão metformina. Os tecidos do animal não apresentaram alterações

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 25

Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced...

importantes. A melhora da glicemia em animais diabéticos com o uso do suco de S. dulcis pode estar em parte
relacionada aos constituintes fenólicos como rutina, quercetina e ácido clorogênico, que apresentam atividade
hipoglicêmica.
Palavras-chave adicionais: Polifenóis; Antioxidante; Cromatografia; Diabetes mellitus.

INTRODUCTION 2016). A review article published on antidiabetic
activity of plant extracts reported the aqueous
Diabetes mellitus accounts for more than 80% of extract of S. dulcis fruit in dogs (Barbosa-Filho et
premature deaths from chronic non-transmittable al., 2005). Bibliographical survey conducted on
diseases worldwide. In 2017, it was found that the use of medicinal plants in Suriname identified
around the world, there were 451 million people a report of antidiabetic action of S. dulcis, but
affected with this disease and the projection for without evidence through preclinical or clinical
the year 2045 is 693 million people with diabetes studies (Mans, 2012).
between the ages of 18 and 99 years (IDF, 2017).
The ethanolic extract of Spondias pinnata
In nature, there is a large list of plants with significantly reduced the blood glucose level of
antidiabetic activity, notably due to its content in Swiss albino rats as compared to the diabetes
secondary metabolites, especially in antioxidants control group demonstrating a remarkable
(Oliveira & Vencio, 2014). The great diversity potential for the treatment of diabetes mellitus.
of existing plant chemical compounds points However, the authors point out that further
to a variety of mechanisms of action possibly studies are required to explore its active
involved in the reduction of blood glucose ingredients responsible for the beneficial actions
(Negri, 2005). and the mechanisms involved in its antidiabetic
actions (Devi et al., 2016).
In addition, studies with fruit species have
identified the presence of secondary metabolites In this context, this study investigated the
with mediating action on cellular chemoprotective possible hypoglycemic activity of S. dulcis and
activity, by the presence of phenols, tannins determined which chemical compounds could
and flavonoids (Clerici & Carvalho-Silva, 2011; be responsible for this action. Thus, to add value
Morais et al., 2013). to this native edible fruit from Northeastern
Brazil, facing the needs of the consumer market
It has been shown that the polyphenols in products with functional properties aimed at
galatocatechin, epicatechin, epigallocatechin people with diabetes mellitus.
and epigallocatechin gallate have antidiabetic
activity (Sabu et al., 2002). 3-caffeoylquinic MATERIALS AND METHODS
acid (chlorogenic acid) extracted from Cecropia
obtusifolia (Andrade-Cetto & Wiedenfeld, 2001) Ethical Aspects
and some saponins derived from triterpenoids This study was submitted to the Ethics
(Connolly & Hill, 2001) showed hypoglycemic Committee on Use of Animals (CEUA) of Ceará
effect. State University and approved under No.
42582992/2016.
The genus Spondias (Anacardiaceae)
is constituted by exotic plants with edible Fruits Obtaining
fruits, which are resistant to semi-arid climate The fruits were purchased at the main farmers’
conditions. The golden apple or cajarana market (CEASA) in the municipality of
(Spondias dulcis Parkinson or Spondias cytherea Maracanaú, Ceará, Brazil. This fruit occurs
Sonn.) is native to Polynesia and has been widely seasonally and is not widely sold in retail
distributed to many tropical and sub-tropical commerce. The fruits chosen were between green
regions of the world. The plant is found in many and totally ripe (the point when they are usually
places of Brazil, especially in the Northeastern consumed).
region (Fernandes et al., 2018).
Preparing the Spondias dulcis Fruit Juice
A study revealed a high antioxidant capacity The fruits were washed and disinfested in a
present in the fruit of S. dulcis that was potentially sodium hypochlorite solution (150 ppm). The
active and safe in obtaining a phytocosmetic seeds were discarded and the pulp with the skin
(Oliveira, 2011). Previous studies have reported
on the popular use of S. dulcis stem bark in the
treatment of diabetes (Taylor & Francis Group,

26 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Silva, J.M.A. et al

was ground in a blender without water. The Antioxidant Activity by the DPPH Method
resultant material of S. dulcis was passed through The antioxidant activity was evaluated by the
a sieve and filter paper. Then, it was lyophilized 1,1-diphenyl-2-picrylhydrazyl (DPPH) free
(Liotop L1010 freeze dryer) and the resultant radical scavenging method, using quercetin as the
material named lyophilized fruit juice of S. dulcis standard in the same concentration as the extract,
(LJSD) was weighed and placed in hermetically as described by Yepez et al. (2002). Samples of 3.9
sealed glass jars and stored under refrigeration mL of a methanolic solution (6.5 x 10-5 M) of the
(4º to 10 ºC). The yield obtained from 500 g of the free radical DPPH were placed in a series of test
peeled fruit was 260 mL of concentrated juice, tubes. Then 0.1 mL of the methanolic solution of
which frozen and lyophilized, yielded 18.75 g of LJSD samples at concentrations of 10,000, 5,000,
dry juice (7.2%). LJSD solution (~40mg/mL) was 1,000, 500, 100, 50, 10 and 5 ppm were added to
administered to the animals, corresponding to each tube. After waiting 60 min, the absorbance
200 mg aqueous extract of S. dulcis/kg of animal was read in the UV-visible spectrophotometer
weight. (Thermo Scientific Genesis 10S) at 515 nm. We
then calculated the Scavenging Index of the
Phytochemical Analysis sample in percent (SI%) using the formula: SI%
The phytochemical analysis of the extract was = (ADPPH – ASAMPLE/ADPPH) x 100, where A is the
performed according to the method proposed by absorbance after 60 min.
Matos (2009). This consists of qualitative analyses
with specific reagents, where the results are Antioxidant Activity by the ABTS Method
determined by the formation of precipitates and The assay with 2.2’-azino-bis (3-ethylbenzo-
color variation. thiazoline-6-sulphonic acid) (ABTS) radical was
performed according to the method of Re et al.
Determination of Total Phenols (1999). The cajarana juice was evaluated for its
The total phenols were measured by spectroscopy antioxidant capacity by the scavenging the ABTS
in the visible region according to the method of radical. The test was started by preparing the
Folin-Ciocalteu (Roesler et al., 2007). The Folin- radical, using 5 mL of the ABTS solution was
Ciocalteu freeze-dried aqueous extratc (7.5 mg) mixed with 88 μL of sodium persulfate solution
was dissolved in methanol, transferred to a and kept in the dark in a refrigerator for 16 h.
25 mL round-bottom volumetric flask and the After this, 1 mL of this solution was added to
final volume was completed with methanol. An 99 mL of ethanol. For the stock solution, 15 mg
aliquot of 100 μL o this solution was stirred with of LJSD was weighed and 1.5 mL of ethanol
500 μL of Folin-Ciocalteu reagent for 30 seconds, was added, after which serial dilutions were
followed by addition of 6 mL of distilled water performed to obtain eight concentrations: 10,000,
and 2 mL of 15% Na2CO3. This mixture was stirred 5,000, 1,000, 500, 100, 50, 10 and 5 ppm. Then, 30
for 1 min. Then the volume was completed to 10 μl of each concentration solution was added to 3
mL with distilled water. After 2 h the absorbance mL of ABTS and kept in the dark for 6 min., after
of the samples was determined in a UV-visible which the absorbance was read at 734 nm. The
spectrophotometer (Thermo Scientific Genesis test was carried out in triplicate. At the end, the
10S) at 750 nm, against the blanks methanol and 50% inhibitory concentration of free radical was
all the reagents. All the analyses were performed calculated by linear regression analysis.
in triplicate.
High-performance Liquid Chromatography
Flavonoid Contents with Diode Array Detection (HPLC-DAD)
The method described by Funari & Ferro (2005) The phenolic compounds in the LJSD were
was used to determine the flavonoid content, quantified by HPLC-DAD. The analytic standards
using 2 mg of aqueous extract of S. dulcis at a chlorogenic acid, rutin and quercetin were
concentration of 2 mg/mL (obtained by dissolving purchased from Sigma Chemical Co. (St. Louis,
20 mg of the freeze-dried aqueous extract in 10 MO, USA). The solvents used in the extraction
mL of ethanol), mixed with 1 mL of an aqueous were analytical grade (acquired from Vetec,
solution of aluminum chloride. After 30 minutes, São Paulo, Brazil), and HPLC grade solvents
the solution was analyzed in the same UV-visible were used in the chromatography (supplied
spectrophotometer (Thermo Scientific Genesis by J.T. Baker). The water was purified with a
10S) at 425 nm. Milli-Q system (UV Direct3). All the samples and

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Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced...

solutions used in the HPLC analyses were first water, hydrophilic cotton, a beaker, aluminum
filtered through a 0.45 µm nylon membrane and foil (protection against light), 1.5 mL Eppendorf®
a 0.22 µm Millipore membrane, respectively. All centrifuge microtubes and microtube holders.
the analyses were performed in triplicate.
Preparation Plasma for Glycemic Analysis
A Shimadzu Prominence SIL-20A After collection, the blood samples were left at
autosampler (Shimadzu, Kyoto, Japan) was used, rest for 30 min, after which the first centrifugation
equipped with Shimadzu LC-20AT reciprocating was performed (13,000 rpm for 3 min). The
pumps, connected to a DGU 20A5 degasser with supernatant was collected in new tubes and
CBM 20A integrator, SPD-M20A diode array centrifuged again (11,000 rpm for 2 min) and the
detector and running the LC Solution 1.22 SP1 supernatant from each tube was again collected
software. The chromatographic analyses were for analysis of glycemia.
performed using a Luna C18 reversed-phase
column (Phenomenex®) (4.6 X 250 mm, 5 µm). Design in vivo Experiment
The mobile phases C and D were acetonitrile After induction of diabetes, the groups, with at
and Milli-Q water, acidified to pH 2.8 with least six animals, were separated and identified
phosphoric acid. The following solvent gradient for experimentation for 14 days . The used dose
was used: 0-15 min, an isocratic elution with of the aqueous extract of S. dulcis was 200 mg/kg
C:D (20:80 v/v); 17-25 min, linear variation of body weight.
until C:D (40:60 v/v); and 25-40 min, another
isocratic elution with C:D (20:80 v/v). The flow Groups of Animals:
rate was 1.0 mL/min, with injection volume 1. Control: health animals - mice without any
of 20 L and wavelength of 350 nm. Standard
reference solutions were prepared in HPLC- treatment (n = 6)
grade methanol in concentrations ranging from 2. Untreated: mice with diabetes induced by
0.00032-1.0 mg/ml for rutin; 0.000064-0.2 mg/
mL for quercetin; and 0.008-1.0 mg/mL for alloxan (n = 6)
chlorogenic acid. The chromatographic peaks 3. Metformin: mice treated with 200 mg/kg of
were confirmed by comparing the retention
times with the reference standards and by the metformin (n = 6)
DAD spectrum (200 to 400 nm). The calibration 4. LJSD: mice treated with 200 mg/kg aqueous
curves were: chlorogenic acid =4.10-8X + 0.0086
(r=0.9993); rutin =4.10-8 X + 0.005 ( =0.9996); and extract of S. dulcis (n = 6)
quercetin =2.10-8X - 2.10-5 ( = 1). The aqueous Group I. Normal healthy mice given only
extract of the S. dulcis fruits was analyzed in
methanol at a concentration of 50 mg/mL. The vehicle (1% gum acacia).
samples were analyzed in triplicate and the mean Group II. Diabetic control mice.
areas under the peaks were measured. Group III. Diabetic mice of this group

Induction of Diabetes with Alloxan were given a single dose of glibenclamide (600
The mice were weighed on the day before the µg/kg body weight) 1 ml with vehicle by oral
inducement and were deprived of food for 8 h. administration daily, for 45 days.
beforehand. The diabetes mellitus was induced
by intraperitoneal administration of the reagent Group IV. Diabetic mice of this group
alloxan monohydrate (Sigma), at doses on two were given single dose of ethanolic leaf extract
consecutive days of 150 mg/kg and 200 mg/ of Phyllanthus amarus (400 mg/kg body weight)
kg of weight, respectively. Then, blood samples 1ml with vehicle by oral administration daily, for
were drawn at intervals of 30, 60 and 120 min to 45 days.
analyze the change in glycemia with time. The
results indicated that the dose of 200 mg/kg of Biochemical Glycemia Analysis
animal weight was the best for further testing, The glycemia was analyzed by the K082
based on two-way ANOVA. colorimetric method, identified by UV
spectrophotometer visible, with the use of a
Blood was drawn from each mouse with a Biotek reader. The results were interpreted
Pasteur pipette in the orbital plexus. Besides the according to the technical recommendations
pipette, the other materials used were distilled for the reagents supplied in the Bioclin® kit for
serological analysis of glucose (Bioclin, 2016).
After seven days, the induction of diabetes was
confirmed by glycemia values ≥ 200 mg/dL (time
= 0). Further blood samples were obtained after
14 days and submitted to the same tests.

28 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Silva, J.M.A. et al

Monitoring Weight and Ingestion of Water RESULTS AND DISCUSSION
and Food by the Animals
The water and food ingestion were measured The phytochemical analysis of the freeze-
daily and the body weight was determined every dried S. dulcis juice revealed the presence of
seven days. The consumption of standard mouse phenols, condensed tannins, catechins, flavones,
chow was expressed in grams/animal/day and flavonols, xanthones and saponins. Table 1
of water in mL/animal/day. summarizes the quantitative analysis of the total
phenols, flavonoids and antioxidant activities of
Histological Tests the aqueous extract of S. dulcis. All the tests were
At the end of the experiment, the animals performed in triplicate.
were euthanized and tissue samples were
collected from the liver and pancreas. The The analysis of the constituents by
isolated fragments were fixed in 10% neutral HPLC-DAD (Table 2) indicated the presence
formalin and embedded in paraffin blocks for of chlorogenic acid, rutin and quercetin of the
conventional histological processing. Sections aqueous extract of S. dulcis.
with thickness of 5 μm were obtained and
stained with hematoxylin-eosin (HE). The slides It can be noted that chlorogenic acid
were examined to identify histological changes predominated over rutin and quercetin,
with a Nikon YS2 light microscope and the respectively. Figure 1 contains the chromatogram,
corresponding images representative of each with peaks 1, 2 and 3 representing, respectively,
organ were captured with a Nikon Coolpix L14 chlorogenic acid, rutin and quercetin.
digital camera with 7.1 megapixels.
In a study conducted in the Amazon region
Statistical Analysis with 15 fruits, including S. dulcis, the authors
The data were expressed in percentage, mean found total phenol levels in this fruit considered
and standard deviation (SD). The significance of to be low. These levels were about two times
differences between the groups was determined higher in pineapple, passion fruit and tangerine
by analysis of variance ANOVA, with p <0.05 compared with the level in the S. dulcis in this
being considered significant. study. Additionally, these fruits did not present
strong antioxidant activity, similar to the results
found for Cajarana by the ABTS and DPPH
methods. The content of total phenols found in

Table 1- Content of total phenols (TP), flavonoids (TFlav) and antioxidant activities (EC50) by two
methods of the lyophilized juice of Spondias dulcis (LJSD)

Samples TP TFlav EC50 ± SD (µg/mL) EC50 ± SD (µg/mL)
LJSD ABTS
(mg GAE/g extract ± SD) (mg QE/g extract ± SD) DPPH
306.18±3.14
47.86±0.44 9.53±0.04 318.70±4.82

Quercetin - - 5.0±0.18 1.79±0.02

LJSO = Spondias dulcis fruit juice; TF = total phenols content; GAE = gallic acid equivalent; FlavT = total flavonoids content;
QE = quercetin equivalent; EC50 = median effective concentration; SD = standard deviation of the mean.

Table 2- Quantification and retention time of this study was two to three times higher than
chlorogenic acid, rutin and quercetin of the lyophilized found in the pulp of Caryocar brasiliense (20.88 ±
3.451 mg GAE/g extract) and Annona crassiflora
juice of Spondias dulcis (16.91 ± 0.81 mg GAE/g extrac-). The quantity
of total phenols was similar to that found in S.
Compounds LJSD RT purpurea (55.0 ± 2.1 mg GAE/g extract) and S.
Chlorogenic Acid (mg/g dry extract) (min) tuberosa (44.6 ± 2.7 mg GAE/g extract) , as well
as in Genipa americana (47.94 ± 1.81 mg GAE/g
0.354 ± 0.002 3.83 extract), while a study carried out with the
fruit of Spondias pinnata for tests with diabetic
Rutin 0.160 ± 0.003 6.35 rats indicated the presence of a phenolic total

Quercetin 0.006 ± 0.001 22.61
RT = retention time

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 29

Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced...

Figure 1- Representative high-performance liquid chromatography profile of the
lyophilized juice of Spondias dulcis fruit. Chlorogenic acid (tR = 3.83 min, peak 1),

Rutin (retention time-tR = 6.35min, peak 2) and quercetin (tR = 22.61 min, peak 3).

of 42.60 mg GAE / 100 g and 14.80 mg GAE / in normal healthy rats remained significantly
100 g flavonoids (Devi et al., 2016). Differences lower throughout the study. p < 0.05 and Diabetic
in the levels of phenolic compounds in samples control = Alloxan-induced diabetic rats (150 mg/
of the same species can result from growing kg).
conditions, cultivar and maturity of the fruits,
besides the measurement method (solvent used Significant reduction in blood glucose
for extraction and polyphenol used as standard levels was observed in blood samples of animals
for quantification). Despite the presence of treated with LJSD for 14 days (Table 3). From day
antioxidant phenolic compounds such quercetin, 0 to 14 significant (p < 0.05) decrease in levels of
rutin and chlorogenic acid, their concentrations glucose was observed in blood samples of animals
in the aqueous extract were too low to confer treated with LJSD (200 mg/kg) and metformin
meaningful antioxidant activity. (200 mg/kg) when compared with glucose levels
in blood samples of diabetic animals, which were
Table 3 reports the data on glycemia, untreated.
weight, water and feed ingestion of the animals
during the experiment. The statistical analysis All mice with induced diabetes present
was performed with glucose level information the glucose levels of blood samples increased
from blood samples collected in the first day comparing in the start and at the end of the
of experiment and after 14 days. Values are experiment. However, at the end (t = 14 days),
expressed as mean ± SEM. Comparison was the glycemic level varied significantly among the
made between glucose levels in blood samples groups when compared to the initial values (t =
of alloxan-induced diabetic rats with LJSD and 0 days). In the untreated animals, the glycemia
metformin treated animals. Blood glucose levels increased by 29.3%, while in the group that
received metformin it rose 12.5% and, and in the

Table 3- Changes in blood glucose levels, body weight, food and water intake, in control, diabetic and diabetic
mice treated with Spondias dulcis lyophilized juice and metformin. Values are mean ± S.E.M. (n=6)

Blood Glucose Blood Glucose Initial Final Food Water
(mg/dL) (mg/dL) weight (g) weight (g)
Groups t = 0 day t = 0 day t = 14 days (g/mouse/ (mL/mouse/
t = 14 days
day) day)

Control 87.43±12.75bB 121.14±23.03cA 29.67±2.60 30.69±2.65 3.90±0.36 33.36±0.51
Untreated 297.14±43.38aB 386.14±94.18aA 29.05±2.67 30.86±2.85 8.53±0.52 34.88±4.14
MET 311.00±44.63aB 350.00±97.32aA 28.57±1.82 29.08±2.10 8.22±0.33 31.17±4.63

LJSD 302.83±57.99aB 270.33±74.61A 30.25±2.86 31.61±3.79 7.43±0.29 25.52±5.28

MET = metformin treated animals; LJSD = treatment with lyophilized juice of S. dulcis. The lower-case letters compared
intergroup data (rows) and upper case with respect to time (columns). Equal letters did not present significant differences
(p <0.05) by Tukey’s test and Student’s t, respectively.

30 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Silva, J.M.A. et al

group treated with aqueous extract of S. dulcis abnormal patterns for each type of tissue were
it increased 10.9%. Then, there was a protection identified among the groups of diabetic animals.
by cajarana juice of 18.4% a little better than
metformin, the standard drug, that was 16.8%. Figure 3 (E, F, G, H) show the histological
sections of pancreas tissues. No alterations or
Between t = 0 days and t = 14 days, with abnormal patterns for each type of tissue were
respect to the weight of the animals, no significant identified among the groups of diabetic animals.
differences were found between the initial and
final weights in any of the groups. The average Hypoglycemic effects of quercetin, rutin
daily feed consumption in the control (healthy) and chlorogenic acid were identified previously
group was 3.9 g/animal and the water intake was in studies involving diabetic animals. For
4.38 mL/animal, compatible with values reported example, rutin was associated with improved
in the literature. However, among the diabetic hyperglycemia and dyslipidemia, while inhibiting
animals in general, the feed consumption doubled the progression of liver and heart dysfunction in
and the water consumption rose almost 7-fold STZ-induced diabetic rats (Fernandes et al., 2010).
between the start and end of the experiment. The
feed consumption by the LJSD group declined A study involving administration of extracts
by 20.25% and 28.21% in relation to the MET and from Cecropia pachystachya leaves in alloxan-
Control groups, respectively. Likewise, the daily induced diabetic rats showed hypoglycemic
water consumption among the diabetic animals and antioxidant effects, which confirmed the
was lower in the LJSD group (25.52 mL/animal) traditional use of the plant in the treatment of
than in the MET (30.39 mL/animal) and Control diabetes, due to the presence of chlorogenic acid
groups (33.36 mL/animal). and C-glycosylated flavonoids (Aragão et al.,
2010).
Figure 2 (A, B, C, D) show the histological
sections of liver tissues. No alterations or The beneficial effects of several flavonol
glycosides have been demonstrated in relation
to diabetes mellitus, by acting at multiple

Figure 2- Histological sections of the liver of the mice at the end of the experiment (14 days). A 31
= Control; B = untreated DM; C = DM treated with metformin; D = DM treated with aqueous
extract of Spondias dulcis.

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Antidiabetic effect of fruit juice of Spondias dulcis in alloxan induced...

Figure 3- Histological sections of the pancreas of the mice at the end of the experiment
(14 days). E = Control; F = untreated DM; G = DM treated with metformin; H = DM

treated with lyophilized juice of Spondias dulcis.

sites of glucose regulatory pathways, such as a component of a phytocosmetic also found
as glucose tolerance, glycogen biosynthesis, the presence of rutin and chlorogenic acid in this
glucose uptake and insulin release A study with fruit, and these compounds were associated with
diabetic rats indicated that flavonoids can have antioxidant activity (Oliveira, 2011).
a dual mechanism of action on glycemia, acting
as a secretagogue and mimetic agent of insulin Diabetes mellitus interferes in the
(Cazarolli et al., 2009). Treatment with quercetin physiological control mechanisms, leading
(5 to 20 mg/kg, twice a day for 30 days) in to polyphagia, polydipsia and polyuria. The
rats with diabetes induced by streptozotocin administration of insulin had a regulatory effect
prevented hyperglycemia (Bhutada et al., by reducing the consumption of food and water
2010). A study conducted with extracts from along with the body weight of diabetic rats (Brief
leaves of the white mulberry tree (Morus alba) & Davis, 1984).
administered to diabetic rats revealed that
chlorogenic acid and rutin might account for as Reports of experiments and epidemiological
much as half the observed anti-diabetic activity evidence suggest that diets rich in flavonoids,
observed (Hunyadi et al., 2012). The treatment such as quercetin, can promote prevention and
with quercetin of rats with diabetes induced by treatment of cardiovascular diseases, cancer,
streptozotocin had a protective effect on pancreas and renal and hepatic insufficiency, through
cells, possibly by reducing the lipid peroxidation protective action against cell damages (Behling &
and production of nitric oxide and increasing the Sendão, 2004).
activity of the antioxidant enzymes glutathione
peroxidase, superoxide dismutase and catalase Finally, the consumption of peach and
(Coskun et al., 2005). plum aqueous extract, both rich in polyphenols,
protected rats against a combination of metabolic
An experiment performed with S. dulcis disturbances, including hyperglycemia, insulin
and leptin resistance, dyslipidemia and oxidation
of low-density lipoproteins (Noratto et al., 2015).

32 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Silva, J.M.A. et al

CONCLUSION Bioclin. Glicose monoreagente K082-2. Bioclin p. 1-6.
2017
The lyophilized juice of S. dulcis was able to
reduce the glycemia of diabetic animals by Brief, D.J. & Davis, J.D. Reduction of food intake
similar percentage as diabetic animals treated and body weight by chronic intraventricular insulin
with metformin. These findings indicate that infusion. Brain Research Bulletin, v. 12, p. 571-575.
the fruit juice has improved the glycemia of 1984.
diabetic animals, which can be exploited as a
coadjuvant in the treatment this disease. The Canuto, G.A.B.; Xavier, A.A.O.; Neves, L.C. & Benassi,
observed effect on glycemia with the use of M.T. Caracterização físico-química de polpas de frutos
the aqueous extract of S. dulcis may be in part da Amazônia e sua correlação com a atividade anti-
related to the phenolic constituents, such as radical livre. Revista Brasileira de Fruticultura, v. 32,
rutin, quercetin and chlorogenic acid, already p. 1196-1205. 2010.
known as hypoglycemic compounds. Further
research needs to be performed to understand Cazarolli, L.H.; Folador, P.; Moresco, H.H.; Brighente,
the mechanisms of action of the Cajarana fruit I.M.C.; Pizzolatti, M.G. & Silva, F.R.M.B., Mechanism
juice and their components. of action of the stimulatory effect of apigenin-6-C-
(2″-O-α-l-rhamnopyranosyl)-β-l-fucopyranoside on
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naturais hipoglicemiantes. Brazilian Journal of
Pharmaceutical Sciences, v. 41, p. 121-142. 2005. Sabu, M.C.; Smitha, K. & Kuttan, R. Anti-diabetic
activity of green tea polyphenols and their role in
Noratto, G.; Martino, H.S.; Simbo, S.; Byrne, D. & reducing oxidative stress in experimental diabetes.
Mertens-Talcott, S.U. Consumption of polyphenol-rich Journal of Ethnophamacology, v. 83, p. 109-116. 2002.
peach and plum juice prevents risk factors for obesity-
related metabolic disorders and cardiovascular disease Taylor & Francis Group, Plants with anti-diabetes
in Zucker rats. Journal of Nutritional Biochemistry, v. mellitus properties. ISBN: 978-1-4822-4990-3 (eBook -
26, p. 633-641. 2015. PDF). 2016.

Oliveira, J.E.P. & Vencio, S. Diretrizes da Sociedade
Brasileira de Diabetes: 2013-2014. A & C Farmacêutica
Service 2014-05. 2014.

34 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p.35-39, 2020.
www.aceci.com.br

Artigo Científico/ Scientific Article

Verificação da Aplicação de Isomalte e Xilitol como Substitutos do
Açúcar na Formulação de Pirulitos

Aline Ribeiro Pinheiro, Eurilany Silva de Oliveira & Andrea Cardoso de Aquino

Departamento de Engenharia de Alimentos, Universidade Federal do Ceará, Av. Mister Hull, 2977, Campus
Universitario do Pici, bl. 858, Fortaleza, Ceará, CEP 60356-000, Brazil

(Aceito para publicação em 25/06/2020)

Autor para correspondência: Eurilany Oliveira, e-mail: [email protected]

Pinheiro, A.R.; Oliveira, E.S. & Aquino, A.C. Verificação da aplicação de isomalte e xilitol como substitutos do
açúcar na formulação de pirulitos. ANAIS Academia Cearense de Ciências. v. 4, n. 1, p.35-39, 2020.

RESUMO
O consumo de doces e balas por brasileiros é comum em diferentes faixas etárias, estima-se que cerca de 775
mil toneladas de balas e pirulitos são consumidos por ano. Em contrapartida, a busca dos consumidores por
qualidade de vida associada à saúde e qualidade dos alimentos que consomem é crescente e, tendo em vista
as doenças atreladas ao consumo excessivo de açúcar, a demanda por produtos com menor teor de açúcar tem
sido cada vez mais frequente. Dessa forma, o presente trabalho tem como objetivo elaborar um pirulito a partir
de isomalte e xilitol como substitutos da sacarose e glucose de milho, utilizados na elaboração de pirulitos
convencionais. Nas formulações foram realizadas análises físico-químicas de pH, acidez titulável, sólidos
solúveis totais e umidade, além de análise microbiológica e análise de estabilidade. O uso de isomalte e xilitol se
mostrou viável para a elaboração de pirulitos, apresentando parâmetros físicos, químicos e microbiológicos que
atendem à legislação e aos aspectos sensoriais similares aos produtos presentes no mercado

Palavras-chaves adicionais: Açúcar; Balas; Polióis.

ABSTRACT
Applying Verification of Isomalt and Xylitol as Sugar Substitute in Lollipop Formulation
The consumption of sweets and candies by Brazilians is common in different age groups and it is estimated
that about 775 thousand tons of candies and lollipops are consumed per year. In contrast, the search for
consumers for quality of life associated with the health and quality of the food they eat is growing and, in
view of diseases linked to excessive sugar consumption, the demand for products with lower sugar content
has been increasing frequently. Thus, the present work aims to elaborate a lollipop from isomalt and xylitol as
substitutes for sucrose and corn glucose, used in the elaboration of conventional lollipops. In the formulations
were performed physicochemical analyzes of pH, titratable acidity, total soluble solids and humidity, in
addition to microbiological analysis and stability analysis. The use of isomalt and xylitol was feasible for lollipop
elaboration, presenting physical, chemical and microbiological parameters that comply with the legislation and
sensory aspects similar to the products present in the market.

Additional keywords: Sugar; Candies; Polyols.

INTRODUÇÃO que visa à boa forma. Como resposta para essa
crescente demanda de mercado por alimentos
Há atualmente uma grande preocupação com a mais saudáveis, o uso de substitutos do açúcar
qualidade de vida e a saúde humana, e isso, de têm sido cada vez mais frequente nas formulações.
forma consequente, reflete no cuidado das pessoas Segundo Kawaguti et al. (2008), nas últimas
em relação aos alimentos que consomem (Liboni, décadas o interesse da produção de isomaltulose
2003). Segundo Rosa et al. (2012), o público com tem sido cada vez mais crescente. A isomaltulose
restrições ao consumo de açúcar nunca foi tão é um dissacarídeo redutor, isômero da sacarose,
expressivo, tanto pelo aumento da ocorrência de obtida por conversão enzimática microbiana a
doenças como o diabetes, quanto pelo interesse partir da sacarose.
crescente por uma alimentação menos calórica
O principal derivado da isomaltulose é

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 35

Verificação da aplicação de isomalte e xilitol como substitutos...

o isomalte, também conhecido como Isomalt® Tabela 1- Formulação dos pirulitos sem (controle) e
e Palatinit®, um açúcar-álcool não cariogênico com xilitol
e de baixo valor calórico, obtido por reação de
hidrogenação com a formação de uma mistura Ingrediente F1 F2 F3 F4
equimolar de [6-O-(α-D-glicopiranosil)-D-
sorbitol] e [6-O-(α-D-glicopiranosil)-D-manitol]. Isomalte 20 20 30 40
Sua aplicação no processamento de alimentos
tem sido de interesse dos pesquisadores, uma vez Xilitol - 30 30 30
que pode ser utilizado como adoçante dietético,
não cariogênico e similar a sacarose, mesmo que Água 25 25 25 25
com somente 50% do seu poder edulcorante
(Kawaguti, 2008). Corante vermelho 0,01 0,01 0,01 0,01

O xilitol (1,2,3,4,5-pentaidroxipentano), Aroma de morango 0,01 0,01 0,01 0,01
é um edulcorante bastante utilizado em prepa-
rações que apresenta vantagens quanto a sua se tornar totalmente líquido (80 °C). Em seguida,
utilização (Mussatto, 2002). Bar (1991) definiu foi adicionado o xilitol e a água e, com o auxílio
como uma das suas vantagens em relação à de uma colher de madeira, os ingredientes foram
sacarose, a capacidade de atuar, mesmo em misturados até formar uma calda homogênea. O
baixas concentrações, como conservante de corante e o aroma artificial de morango foram
produtos alimentícios, oferecendo resistência ao adicionados quando a calda atingiu a temperatura
crescimento de microrganismos e prolongando de 130 °C e os ingredientes foram novamente
a vida de prateleira desses produtos, devido sua misturados. Ao atingir temperaturas entre 140
elevada estabilidade química e microbiológica. °C e 142 °C, o aquecimento foi interrompido e a
Neste sentido, o uso desses substitutos no calda obtida foi rapidamente colocada em formas
desenvolvimento de doces, balas e pirulitos se de silicone juntamente com as hastes de plástico.
mostra de encontro aos interesses de mercado.
Os pirulitos enformados seguiram para
Neste contexto, objetivou-se com o presente a etapa de resfriamento, que foi feita sob
estudo, elaborar um pirulito a partir de isomalte refrigeração (16 °C) a fim de agilizar o processo,
e xilitol como substitutos da sacarose e glucose mas que também poderia ser feita à temperatura
de milho, comumente utilizados no processo ambiente. Em seguida, os pirulitos foram
convencional de produção. retirados das formas e pesados, o peso unitário
seguiu uma média de 10g/unidade. As amostras
MATERIAIS E MÉTODOS foram armazenadas até a realização do teste de
estabilidade e das análises microbiológicas, físico-
O desenvolvimento dos pirulitos foi realizado químicas e sensoriais. O processamento ocorreu
no Laboratório de Análises de Alimentos no da mesma forma para todas as formulações e foi
Departamento de Engenharia de Alimentos da ilustrado no fluxograma da figura 1.
Universidade Federal do Ceará (UFC). Foram
desenvolvidas quatro formulações (F1, F2, F3 Estabilidade das amostras
e F4), variando a concentração de isomalte em Para a verificação da estabilidade das formu-
relação ao xilitol, conforme (Tabela 1), a fim de lações, em relação à manutenção da estrutura
verificar como esses açúcares interagiam entre vítrea e dureza, as amostras preparadas foram
si e qual a concentração ideal para estabilizar a colocadas em uma superfície plana antiaderente,
formulação e promover o aspecto vítreo presente à temperatura ambiente, e foi observada a
nos pirulitos convencionais. Os ingredientes estabilidade da conformação das quatro amostras
empregados na formulação foram: isomalte, durante o intervalo de 10 horas. As formulações
xilitol, água, aroma artificial de morango e corante que se mantiveram estáveis nesse intervalo de
Vermelho 40, sendo adquiridos no comércio local. tempo foram escolhidas como ideais para preparo
do pirulito.
Processamento dos Pirulitos
As matérias-primas foram recebidas e armaze- Análises Microbiológicas
nadas adequadamente. Inicialmente foi feito o As análises microbiológicas foram realizadas
preparo do isomalte: o isomalte na forma granular conforme os padrões microbiológicos para
foi aquecido em um recipiente antiaderente até balas, produtos de confeitar, gomas de mascar
e similares, isto é, Coliformes termotolerantes
(45 °C - NMP/g) e Pesquisa de Salmonella sp.

36 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Pinheiro, A.R.; Oliveira, E.S. & Aquino, A.C.

Adição de água Pesagem dos ingredientes F1, F2 e F3 não se estabilizaram e rapidamente
perderam a sua confirmação, como pode ser visto
↓ nas figuras 2, 3 e 4.

Preparo do isomalte A amostra controle (F1), ou seja,
amostra sem adição de xilitol sofreu reação
↓ de caramelização rapidamente, degradando o
→ Adição de xilitol corante e se mostrando inviável. Já as amostras
com quantidades inferiores de isomalte em
↓ relação ao xilitol (F2) e quantidades iguais de
cada ingrediente (F3) rapidamente perderam
Homogeneização sua conformação vítrea ao longo do tempo,
adquirindo textura pastosa. No entanto, a
↓ formulação com isomalte em concentração
superior ao xilitol se mostrou bastante estável,
Enformação mantendo sua confirmação ao longo dos dias
e, em adição, não houve nessa formulação o
↓ processo de recristalização, evidenciando a sua
viabilidade.
Resfriamento
Este teste inicial foi feito apenas para
↓ a definição da formulação adequada para a
elaboração dos pirulitos. Baseado nisso, chegou-
Armazenamento se às formulações finais com cada ingrediente em
quantidades expressas em gramas (Tabela 2).
↓

Pirulito

Figura 1- Fluxograma do processo para obtenção do
pirulito de isomalte e xilitol.

(em 25 g). As análises foram realizadas segundo
metodologia descrita por Silva et al. (2007), cinco
dias depois do produto ser elaborado.

Análises Físico-Químicas Figura 2- Formulação F1 e F2 respectivamente.
Foram realizadas as análises físico-químicas
em triplicata (umidade, acidez titulável, sólidos
solúveis e pH) de acordo com as normas do
Instituto Adolfo Lutz para produtos açucarados.

Análise Estatística
As análises físico-químicas foram submetidas
a análise estatística descritiva onde calculou-
se a média e o desvio padrão. Em seguida, os
dados foram submetidos à análise de variância
(ANOVA) e as médias foram comparadas através
do Teste t Student a 95% de significância.

RESULTADOS E DISCUSSÃO Figura 3- Formulação F3.
Figura 4- Formulação F4.
Estabilidade das amostras
No teste de estabilidade buscou-se avaliar a
compatibilidade entre o isomalte e xilitol, assim
como a quantidade ideal a ser empregada na
formulação para obter o aspecto vítreo do pirulito.
A partir deste primeiro teste definiu-se a F4 como
formulação ideal, ou seja, a formulação com
quantidade de isomalte superior à quantidade
de xilitol, tendo em vista que as formulações

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 37

Verificação da aplicação de isomalte e xilitol como substitutos...

Tabela 2- Formulação ideal para o pirulito Tabela 4- Resultados análises físico-químicas

Ingrediente F4 Análise F0 F4
Isomalte 40 SST (ºBrix) 70,5a ± 0,32 79,8a ± 0,48
Xilitol 30 Umidade 2,63a ± 0,25 2,74a ± 0,04
Água 25 ATT 0,79a ± 0,04 0,77a ± 0,02
Corante vermelho 0,01 pH 5,17a ± 0,04 5,22a ± 0,06
Aroma de morango 0,01
a, b médias com letras iguais, em mesma linha, não diferem
entre si ao nível de 5% de significância para o teste de Tukey.

Análises Microbiológicas obteve diferença significativa entre a formulação
Os resultados das análises microbiológicas com isomalte e xilitol e a formulação controle. O
obrigatórias para a avaliação das condições resultado concorda com Spanemberg (2010), que
higiênico-sanitárias de fabricação de balas, afirma que o teor de umidade desses produtos
produtos para confeitar, gomas de mascar pode variar de 2 a 3%. Esse resultado evidencia
e similares foram organizados na Tabela 3 e a qualidade da aplicação desses substitutos
apresentaram que a formulação escolhida como uma vez que a estabilidade está diretamente
ideal (F4) encontra-se adequada para consumo associada à quantidade de água no produto.
dentro dos padrões legais, não representando Baixas umidades residuais implicam em um
riscos para os consumidores. Foram elaboradas produto quebradiço e com dificuldades durante
duas amostras com a mesma formulação, o processo de formação e altas umidades podem
nomeadas amostra 154 e amostra 147. desencadear alterações durante a estocagem
como a “mela” e a cristalização.
A RDC no12 de 2001, da Agência Nacional
de Vigilância Sanitária (Brasil, 2001) estabelece A acidez e o pH se mantiveram dentro
para produtos, como balas e similares os dos valores previstos nas especificações, além
seguintes padrões microbiológicos: contagem de não diferirem da formulação controle. O
de coliformes a 45 °C/g <3NMP/g e ausência teor de sólidos, como esperado, se manteve alto
de Salmonella sp. em 25 g. Dessa As amostras condizendo com as características de balas duras
analisadas se adequam ao perfil de boa qualidade e pirulitos.
microbiológica expressos pela legislação vigente.
CONCLUSÕES
Análises Físico-químicas
A RDC 265 para balas e similares não faz nenhuma Esta pesquisa mostra que a utilização de isomalte
exigência específica em relação a análises físico- e xilitol na produção de pirulitos é viável do
químicas, porém, essas análises foram realizadas ponto de vista da redução de açúcar nesse
a fim de comparar com o produto convencional produto. Além disso, a formulação apresentou
para verificar a eficiência da substituição dos parâmetros físico-químicos que atendem à
ingredientes, os resultados obtidos foram orga- legislação e aspectos sensoriais similares aos
nizados na tabela 4, comparando-se com a pirulitos convencionais, apresentando boa
formulação F0, testemunha, a qual foi elaborada estabilidade durante toda cadeia produtiva, fato
com o ingrediente convencional açúcar. que evidencia a sua qualidade.

O teor de umidade se mostrou dentro AGRADECIMENTOS
dos padrões para balas duras e pirulitos e não

Tabela 3- Resultados das análises microbiológicas Núcleo de Pesquisa Geraldo Arrais Maia,
NUPGAM.
Análise F0 F4
SST (ºBrix) 70,5a ± 0,32 79,8a ± 0,48 REFERÊNCIAS
Umidade 2,63a ± 0,25 2,74a ± 0,04
ATT 0,79a ± 0,04 0,77a ± 0,02 Bar, A. Xylitol. In: O’Brein Nabors, L. & Gelardi, R.C.,
pH 5,17a ± 0,04 5,22a ± 0,06 eds. Alternative Sweeteners. 2. ed., New York: Marcel
Dekkor Inc., 1991. p. 349-379.

38 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Pinheiro, A.R.; Oliveira, E.S. & Aquino, A.C.

Brasil. Resolução RDC nº 12, de 02 de janeiro de http://dx.doi.org/10.1590/S010040422008000100025.
2001. Aprova o regulamento técnico sobre padrões
microbiológicos para alimentos. Diário Oficial [da] Mussatto, S.I. & Roberto, I.C. Xilitol: Edulcorante
República Federativa do Brasil, Poder Executivo, com efeitos benéficos para a saúde humana. Revista
Brasília, DF, 10 jan. 2001. Disponível em:http://elegis. Brasileira de Ciências Farmacêuticas, v. 38, n. 4, p. 401-
anvisa.gov.br/leisref/public/showAct.php?id=144& 413, 2002.
word =. Acesso em: 06 jul. 2019.
Liboni, L.M.P. & Kun, Y.P. Frutooligossacarídeos:
Brasil. Resolução nº 265, de 22 de setembro de 2005. implicações na saúde humana e utilização em
Regulamento técnico para balas, bombons e gomas alimentos. Ciência Rural, v. 33, n. 2, p. 385-390, 2003.
de mascar. Diário Ofi cial [da] República Federativa
do Brasil, Poder Executivo, Brasília, DF, 23 set. 2005. Rosa, N.C.; Trintim, L.T.; Corrêa, R.C.G.; Vieira, A.M.S.
Disponível em: http://e-legis. anvisa.gov.br/leisref/ & Bergamasco, R. Elaboração de geleia de abacaxi com
public/showAct.php?id=18824&word=. Acesso em: hortelã zero açúcar: processamento, parâmetros físico-
06 jul. 2019. químicos e análise sensorial. Revista Tecnológica, p.
83-89, 2011. Edição Especial V Simpósio de Engenharia,
INSTITUTO ADOLFO LUTZ. Normas analíticas: Ciência e Tecnologia de Alimentos.
métodos químicos e físicos para análise de alimentos.
3. ed. São Paulo, 1985. v.1, 533p. Silva, N. Manual de métodos de análise microbiológica
de alimentos. 3. ed. São Paulo: Varela, 2007. 544 p.
Kawaguti, H.Y. & Sato, H.H. Produção de isomaltulose,
umsubstitutodasacarose,utilizandoglicosiltransferase Spanemberg, F.E.M. Planejamento de experimentos
microbiana. Quím. Nova, São Paulo, v. 31, n. 1, p. com mistura no estudo da vida útil de balas duras.
134-143, 2008. Available from <http://www.scielo. 2010. 120 f. Dissertação (Mestrado em Engenharia de
br/scielo.php?script=sci_arttext&pid=S010040422008 Produção) - Faculdade de Engenharia, Arquitetura e
000100025&lng=en&nrm=iso>. access on 25 June 2020. Urbanismo, Universidade Metodista de Piracicaba,
Santa Bárbara D’oeste. 2010.

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 39

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 40-47, 2020.
www.aceci.com.br

Artigo Científico/ Scientific Article

Bronchodilator Activity of the Essential Oil from Lippia sidoides in
Bronchial Isolated from Swine Sus scrofa domesticus

Luís Pereira-de-Morais*, Andressa de Alencar Silva, Renata Evaristo Rodrigues da Silva, Carla
Mikevely de Sena Bastos, Isaac Moura Araújo, Roger Henrique Sousa da Costa, Francisco Assis

Bezerra da Cunha, José Henrique Leal-Cardoso & Roseli Barbosa

Universidade Estadual do Ceará

(Aceito para publicação 19/07/2020)

Author for correspondence: Luís Pereira de Morais, e-mail: [email protected]

Pereira-de-Morais, L.; Silva, A.A.; Silva, R.E.R.; Bastos, C.M.S.; Araújo, I.M.; Costa, R.H.S.; Cunha, F.A.B.; Leal-
Cardoso, J.H. & Barbosa, R. Bronchodilator activity of the essential oil from Lippia sidoides in bronchial isolated
from swine Sus scrofa domesticus. ANAIS da Academia Cearense de Cências, v. 4, n. 1, p.40-47, 2020.

ABSTRACT
Natural products have molecules with therapeutic properties. Among the natural products, the plant Lippia
sidoides Cham (Verbenaceae), popularly called Rosemary Pepper, is used in folk medicine as antiseptic agent.
Some studies have shown that L. sidoides promotes electrophysiological changes in the smooth muscle of
the airways of rats. However, the effect of L. sidoides on pig airways has not yet been demonstrated. In the
literature it has been described that rodent and pig tissues respond differently to drugs, and that pig tissue is
very similar to human tissue, being an alternative model with less ethical limitations, since pigs are slaughtered
for human consumption. The aim of this study was to investigate the effect of L. sidoides essential oil (EOLs) on
the bronchial respiratory smooth muscle isolated from Sus scrofa domesticus pigs. To evaluate the effect of EOLs,
increasing and cumulative concentrations of 1-3000 µg/mL were administered in bronchial rings, previously
contracted and maintained in presence of KCl (60 mM) or acetylcholine (ACh; 10 µM). It was observed that
the EOLs relaxed, in a concentration-dependent manner, the bronchial preparations pre-contracted by KCl
(60 mM), having their maximum efficiency in the concentration of 1000 µg/mL. For the contraction induced
by ACh, adding at a concentration of 3000 µg/mL, the EOLs relaxed only about 30 % of the contraction. The
EOLs have greater pharmacological potency in electromechanical coupling, with a bronchodilator effect, being
a potential therapeutic agent with action on the respiratory tract. The effectiveness of the method chosen for the
development of the research was also evidenced.

Additional keywords: Pigs; Respiratory smooth muscle; Organ bath; Lippia sidoides; Essential oil.
RESUMO

Atividade broncodilatadora do óleo essencial de Lippia sidoides em brônquios isolados
de suínos Sus scrofa domesticus

Os produtos naturais apresentam moléculas com propriedades terapêuticas. Dentre os produtos naturais, a
planta Lippia sidoides (Verbenaceae), popularmente denominada alecrim-pimenta, é usada na medicina como
agente antisséptico. Alguns estudos demonstraram que, a L. sidoides Cham promove alterações na contratilidade
do músculo liso de vias aéreas de ratos. No entanto, o efeito da L. sidoides em vias aéreas de porco ainda não foi
demonstrado. Na literatura encontra-se descrito que tecido de roedores e porcos responde diferentemente aos
fármacos, e que o tecido de porco é muito semelhante ao humano, sendo um modelo alternativo com menos
limitações éticas, uma vez que, os suínos são abatidos para o consumo humano. O objetivo deste estudo foi
investigar o efeito do óleo essencial de L. sidoides (OELs) sobre o músculo liso respiratório bronquial isolado
de porcos da espécie Sus scrofa domesticus. Para avaliar o efeito do OELs, foram administradas concentrações
crescentes e cumulativas de 1-3000 µg/mL em anéis de tecido bronquial, previamente contraídos por e man-
tidos na presença de KCl (60 mM) ou acetilcolina (ACh; 10 µM). Observou-se que o OELs, relaxou de forma
concentração dependente as preparações bronquiais pré-contraídas por KCl (60 mM), tendo sua eficácia máxima
na concentração de 1000 µg/mL. Já na contração induzida pela ACh (10 µM), adicionando uma concentração
de 3000 µg/mL, o OELs relaxou apenas cerca de 30% da contração. O OELs apresenta potência farmacológica
maior em acoplamento eletromecânico, com efeito broncodilatador, sendo um potencial agente terapêutico com
ação no trato respiratório. Evidenciou-se também a eficácia do método escolhido para o desenvolvimento da
pesquisa.
Palavras-chave adicionais: Suínos; Broncodilatação; Banho de órgãos; Lippia sidoides; Óleo essencial.

40 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Pereira-de-Morais, L. et al.

INTRODUCTION contributing to the advancement in research
with bronchodilator drugs, derived from natural
The plant species Lippia sidoides Cham is a products. It also aimed to contribute with the
shrub vegetable, popularly known as Rosemary adoption of alternative methods, ethically more
Pepper. Its leaves are thick-sawn, with variable recommendable, for using as laboratory animals.
dimensions (approximately up to 8 cm), covered
with small hair-like filaments on both sides; its MATERIAL AND METHOD
flowers are yellowish-white, small, and are found
in subglobous and subpiramidal inflorescences 1- Vegetable Material and Essential Oil
(Craveiro et al., 1981). It is found in abundance in Extraction
the northeastern hinterland, being more common
in the States of Ceará and Rio Grande do Norte. The botanical material from L. sidoides was
Lippia sidoides is widely used in folk medicine, collected in the Horto de Plantas Medicinais,
mainly as an antiseptic (Lemos et al., 1990; Lacoste (Garden of Medicinal Plants) from the Laboratório
et al., 1996). Its leaves are generally used topically, de Pesquisa de Produtos Naturais – LPPN
as home remedies to treat acne, wounds, skin and (Laboratory of Research of Natural Products –
scalp infections. Its infusion has been used in folk LPPN), from the Universidade Regional do Cariri
medicine as an aromatherapy agent for allergic - URCA (Regional University of Cariri – URCA).
rhinitis, and in the treatment of vaginal infections, The plant collection period was chosen according
mouth and throat (Matos & Oliveira, 1998). to the time in which the highest yield of essential
oil is produced, which was made in June 2013.
According to the literature some already After the specie identification, a sample was
proven biological actions of the Lippia sidoides deposited at the Herbarium Dárdano de Andrade
species, such as: antimicrobial activity on Lima, URCA, and identified under registration
Staphylococcus aureus (Silva et al., 2010), antifungal number # 6480.
on Curvularia luneta (De Souza Ferreira et al.,
2018), insecticide on Rhodnius prolixus (Chagas 2- Essential Oil of Lippia sidoides
disease vector) (Figueiredo et al., 2017), rat sciatic Essential oil from L. sidoides (EOLs) was obtained
nerve excitability inhibitor (Barbosa et al., 2017), by hydrodistillation in a Clevenger type
antispasmodic effect on rat trachea (Teófilo, 2012). apparatus. The leaves were cut into fragments
of approximately 1 cm2, subsequently immersed
Based on the already known myorelaxant in distilled water, submitted to extraction for
effect on the smooth muscle of rodent airways, the approximately 2 h. Then, the essential oil was
present investigation tried to elucidate whether treated with anhydrous sodium sulfate, filtered
the L. sidoides species presents this same effect in through cotton, transported by Pasteur pipette to
swine airways; since there is a similarity between amber glass and stored at -20 oC.
pig and that of humans physiology. In addition,
we aimed to replace the use of laboratory animals, 3- Chemical Analysis
thus obeying the rule of 3 Rs (reduce, refine, 3.1- Gas Chromatography coupled to mass
replace); which was initiated by the University
Federation for Animal Welfare (UFAW’s), which spectrometry (GC-MS).
means: reducing the number of animals used in The GC-MS analysis was performed on an XL
research, refining the methodology in order to GC-MS, which operates in EI mode at 70 eV,
reduce the pain and discomfort suffered by and equipped with a split/splitless injector (220 ° C).
seek alternative methods that ultimately replace Helium gas was used as a carrier (1.0 mL min-1).
their use, this being the maximum goal to be A capillary column of HP 5MS (30 m × 0.35 mm,
achieved (Russel & Burch, 1992). film thickness 0.50 mm) and HP Innowax (30 m ×
0.32 mm i.d., film thickness 0.50 mm) were used.
In this study, the pig bronchial tissue from The temperature programmer was the same as
the species Sus scrofa domesticus (Large Whit) one used to analyze the GC. The injected volume
was used, as an alternative model to rat trachea. was 1 μL of the essential oil diluted in chloroform
The pig tissue is characterized as an alternative (1: 10).
method, since the animals used to extract
bronchial tissues are slaughtered for human 3.2- Gas chromatography with flame ionization
consumption. This work aimed to demonstrate detector (GC-FID).
the myorelaxant effect of L. sidoides essential oil
on the smooth muscle of swine bronchial rings, Gas chromatography (GC) was performed with

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 41

Bronchodilator Activity of the essential oil from Lippia sidoides...

Agilent Technologies GCFID 6890N System lung lobe was dissected, and the lateral branches
equipment, equipped with a DB-5 capillary, were removed and placed on TM.
column (30 m × 0.32 mm; 0.50 mm), connected
to an FID detector. The thermal programmer Subsequently, the bronchial segments were
was from 60 °C (1 min) to 180 °C at 3 °C/min; cleaned, and then cut into rings (3 to 5 mm in
injector temperature of 220 °C; 1:10 split rate, length and 3 to 5 mm in diameter). These rings
using Helium as the carrier gas and the flow were horizontally suspended between two
rate: 1.0 mL/min. The volume to be injected was L-shaped stainless steel hooks, and mounted in
1 μL, diluted in chloroform (1:10). Two sample an isolated organ bath with a capacity of 10 mL
replicates were processed in the same way. The of TM with continuous aeration, temperature
relative concentrations of the components were regulation at 37 °C and pH 7.4. The preparation
estimated based on the peak areas of the GC, was one end connected to a force transducer
without using correction factors. through a mobile rod, and the other end to a fixed
base of the equipment. The mechanical muscular
3.3- Component Identification responses (generation of strength or relaxation)
The constituent identification was performed were transformed by the transducer into an
based on the retention index (RI), determined electrical signal. The transducer was connected to
with reference to the homologous series of a differential amplifier (DATAQ, model PM-1000,
n-alkanes C7-C30, under identical experimental USA), and this to the input of a digital analog
conditions. The comparison was made by means converter board (DATAQ DI-200) installed on a
of research at the mass spectrum library (NIST computer, whose collected data were converted
and Wiley), and also at the literature of mass into plots and stored in files using the WINDAQ
spectra. The relative amounts of individual software (DATAQ Instruments, Inc. USA)
components were calculated based on the peak for later analysis. After the preparation, the
GC area (FID response). bronchiole isolated segments were subjected to a
tension of 1 gf (gram/force), and stabilization was
4- Muscle Contractile Changes maintained for a period of 1 h with TM renewal
According to Normative Resolution Concea every 15 min, time necessary for the preparation
No. 30, of February 2, 2016, animal carcasses for adapting to the new conditions.
or part of them, originating from the activities
of slaughterhouses, are exempt from going To evaluate the effect of EOLs, initially two
through the Animal Use and Experimentation responses of the bronchus to 60 mM KCl (K60),
Commission (CEUA), in order to evaluate its the contraction-inducing agent, were obtained,
ethical aspects. in order to demonstrate the tissue good viability.
Afterwards, a third contraction was evoked with
A total of 24 fragments of lungs from adult a contraction-inducing agent which, depending
pigs of S. domesticus, distributed in protocols on the excitation-contraction coupling route to
of three animals, which were obtained from be analyzed, was either KCl (60 mM)-induced
the slaughterhouse Frigorífico Industrial do contraction, for the electromechanical coupling
Cariri, located in the Juazeiro do Norte city, via, or ACh (10 μM)-induced contraction, for
State of Ceará, Brazil. The organ was provided pharmacomechanical cholinergic coupling.
with animals that were slaughtered for meat Reached the steady-state of the third contraction,
consumption. All animals, as well as their meat subsequent and cumulative doses of EOLs
and viscera, were inspected by veterinarians were administered to the preparation at the
before and after slaughter, verifying the animal’s concentrations of: 1, 3, 10, 30, 100, 300, 600, 1000
good health condition. and 3000 µg/mL in different experiments. Soon
afterwards, successive washes were performed
During transportation to the laboratory, the with TM, in order to de-impregnate the agents
lungs were placed in an ice-cold modified Tyrode in study of the bronchial tissue for subsequent
(TM) solution, with the following composition in induction of contraction with K60, in order to
mM: NaCl, 136; KCl, 5.0; MgCl2, 0.98; NaH2PO4, observe the tissue recovery.
0.36; NaHCO3, 11.9; CaCl2, 2.0 and Glucose,
5.5. The nutrient solution was kept constantly 5- Statistical Analysis
aerated by bubbling air, at a temperature of 37 ° Data are expressed as the mean ± S.E.M, n=6 in
C, and pH adjusted to 7.4, using 1M HCl and/or all experimental series. Sigma Plot 11.0 software
1M NaOH. The bronchus of the trunk of a lower was used for statistical analysis and graphics

42 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Pereira-de-Morais, L. et al.

production. Effects were considered statistically (22.63%) were identified as the most abundant
significant if they had the probability of the null constituents of EOLs. According to Dos Santos et
hypothesis lower than 5% (p < 0.05). Student t al. (2015), some factors such as plant age, season
tests and analysis of variance (one or two-way of the year, nutritional availability, genetic factors
ANOVA) were used, followed by Bonferroni’s and climatic factors are significantly influencing
t-test and Holm-Sidak multiple comparisons the chemical composition and essential oil
method, when appropriate. In order to calculate content of aromatic plants.
the IC50, the concentration of the substance which
was capable of producing 50% of inhibition of The genus Lippia has species known for
its maximum effect, a logarithmic interpolation being, in the great majority, producers of essential
for each experiment was performed, and when oils with great diversity of chemical compounds,
not possible, the linear relationship between two such as: thymol, carvacrol, geranial, linalool,
points of the IC50 was performed. ρ-cymene, carvona, neral, limonene, β-caricofene,
oxide of karyophyllene, myrcene and γ-terpinene,
RESULTS AND DISCUSSION which provide broad medicinal properties to
these species (Dos Santos et al., 2015).
1- EOLs Chemical Characterization
The chemical analysis of the L. sidoides essential In this regard, the L. sidoides essential oil
oil by CG-MS allowed the identification of 30 has been the subject of numerous investigations,
compounds, representing 97.74% of the essential especially for its potential biological activities
oil; their retention indices and percentage attributed to the presence of active ingredients.
composition are shown in Table 1. Thymol The literature reports several biological
was presented as a major constituent (74.88%), properties of essential oil and constituents.
followed by other secondary constituents, such For example, for thymol and carvacrol, the
as: (E)-cariophylene (5.41%), ρ-cimene (5.21%), pharmacological activities are reported: larvicide
eucalyptol (2.39%) and γ-terpinene (1.51%). The (Carvalho et al., 2003), fungicide (Laranjeira et
other constituents had less than 1% of the oil al., 2013), leishmanicide (Farias-Junior et al.,
content. 2012), antibacterial (Lobo et al., 2014), acaricide
(Oliveira et al., 2018), and myorelaxant in rat
Much of the analysis on the chemical trachea (Teófilo, 2012).
composition of the essential oil of L. sidoides, a
native species from the Northeast region of Brazil, Due to the multiplicity of pharmacological
has demonstrated the presence of monoterpene activities of essential oils, the myorelaxant
thymol as the major compound, as observed in activities of important constituents of EOLs have
the present work. A similar result was obtained been also investigated in several preparations.
by Brito et al. (2015), in which thymol was also For example, thymol and carvacrol, in isolated rat
found to be a major constituent. aorta (Peixoto-Neves et al., 2010), and in trachea
of guinea pig (Boskabady & Jandaghi, 2003);
It is noteworthy that thymol (5-methyl-2- 1,8-cineole in rat aorta (Pinto et al., 2009); trans-
(1-methylethyl)-phenol) is a monoterpene found karyophylene, in rat trachea (Pinho-Da-Silva et al.
in numerous aromatic plants. It is biosynthesized , 2012).
from γ-terpinene and ρ-cymene, as well as its
isomer carvacrol (2-methyl-5-(1-methylethyl)- In addition, studies have demonstrate the
phenol), a constituent structurally similar to low toxicity of EOLs (Fontenelle et al., 2007), and
thymol; differing only in the position of the related to this, L. sidoides was included in the
hydroxyl group attached to the aromatic ring list of plants selected by the Government of the
(Nostro & Papalia, 2012). State of Ceará, Brazil, as a herbal medicine, and
is grown in vegetable gardens of plants used in
The results verified for the chemical folk medicine, reinforcing the National Policy
analysis of EOLs in this study, were also similar to of Integrative and Complementary Practices
those described by Oliveira et al. (2018) (thymol: (PNPIC) within the scope of SUS (Costa et
68.45%), Laranjeira et al. (2013) (42.33%) and Veras al., 2002). All of these data contribute to the
et al., (2012) (84.9%), who identified thymol as evaluation of the effect of EOLs in the protocols
the major constituent of EOLs in their respective presented below.
works. However, the results presented differ
from those described by De Lima Guimarães et al. 2- Bronchodilator effect of Lippia sidoides
(2014), in which carvacrol (26.44%) and 1.8-cineol In order to evaluate the influence of EOLs on
contractions induced by K+ and ACh, increasing

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Bronchodilator Activity of the essential oil from Lippia sidoides...

Table 1- Chemical constituents present in the essential oil found in Lippia
sidoides leaves

Compound RIb. RIc. %± SDa
α-thujene 924 924 0.35±0.01
α-pinene 932 929 0.32±0.00
β-pinene 974 972 0.24±0.01
1-octen-3-ol 974 978 0.57±0.00
Myrcene 988 989 0.42±0.00
δ-3-carene 1008 1007 0.08±0.01
α-terpinene 1014 1014 0.57±0.01
ρ-cymene 1020 1022 5.21±0.02
Limonene 1024 1026 0.01±0.00
Eucalyptol 1026 1028 2.39±0.01
γ-terpinene 1054 1057 1.55±0.01
cis-sabinene hydrate 1065 1065 0.08±0.01
Linalool 1095 1099 0.20±0.01
Ipsdienol 1140 1145 0.84±0.03
terpinene-4-ol 1174 1175 0.27±0.02
thymol,methyl ether 1232 1234 0.50±0.00
Thymol 1298 1301 74.88±0.29
thymol acetate 1349 1354 0.15±0.00
α-copaene 1374 1375 0.08±0.01
(E)-caryophyllene 1417 1420 5.44±0.14
Aromadendrene 1439 1439 0.67±0.02
α-humulene 1454 1453 0.36±0.01
allo-aromadendrene 1460 1460 0.07±0.01
γ-muurolene 1479 1476 0.32±0.00
germacrene D 1480 1481 0.06±0.00
Viridiflorene 1496 1495 0.61±0.01
γ-cadinene 1513 1514 0.10±0.00
δ-cadinene 1522 1523 0.17±0.00
Spathulenol 1577 1577 0.36±0.01
caryophyllene oxide 1582 1583 0.85±0.01

Total 97.74

a, Relative proportions of essential oil constituents were expressed as percentages.
b, Retention indices from literature. c, Experimental retention indices (based on

homologous series of n-alkane).

and cumulative concentrations of EOLs 1-3000 of K+ in the extracellular environment promotes
µg/mL were administered to the preparations of a depolarization of the transmembrane potential
swine bronchial muscle previously contracted by by displacement of the K+ electrochemical
KCl (60 mM) or ACh (10 μM). gradient, which opens the ionic channels of the
type voltage-operated Ca2+ channels (CCOV),
Initially, when evaluating the effect of causing the influx of Ca2+, thus promoting
EOLs on KCl-induced contractions of bronchial contraction (Bolton et al., 1999).
smooth muscle, it was found that EOLs were able
to relax 100% of the contraction promoted by When evaluating the EOLs on the
K60 in a concentration dependent manner, when contractions promoted by 10 μM acetylcholine,
compared with the control (Figura 1A). It was it was found that the EOLs did not inhibit 100%
observed that this effect occurred in a statistically to the contraction, even tripling the maximum
significant way, from the concentration of 100 μg concentration of the previous protocol (Figure
/ mL upwards (p <0.001, ANOVA, Holm-Sidak 1B). The relaxation promoted by EOLs in this
method). The IC50 value for this contraction was way was statistically significant only for the
450.49 ± 5.73 μg/mL. It is known that the presence concentrations of 600, 1000 and 3000 μg/mL,

44 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Pereira-de-Morais, L. et al.

being: 15.14 ± 8.23, 20.15 ± 9.88, 30.39 ± 10.51%, Figure 1- Relaxing effect of EOLs on contractions of
the relaxation obtained, respectively (p <0.001, bronchial tissue of Sus scrofa domesticus induced by
ANOVA , Holm-Sidak method). (Figure 1B). K+ and acetylcholine (ACh). (A) Concentration-effect
curve of EOLs, (1-1000 μg/mL) relaxant activity on
These data allow to suggest that EOLs contraction induced by 60 mM KCl (A) or by 10 μM
also have activity, even if reduced, in activation ACh (B) in smooth muscle of isolated swine bronchial
of muscarinic receptors; as a side effect they rings. Values are expressed as mean ± S.E.M, (p <0.001,
promote little or no influx of Ca2+ through one-way ANOVA followed by Holm-Sidak).
ligand-dependent calcium channels, since these
receptors require second messenger inorganic study showed relaxing activity of EOLs in the
triphosphate (IP3), and diacylglycerol (DAG), respiratory tissue of S. scrofa domesticus. Given the
which are activated by ACh (Devi et al., 2011). physiological similarity of the porcine respiratory
tract to that of humans, it is demonstrated that
The results suggest that EOLs have a EOLs have great pharmacological potentiality to
myorelaxant effect on swine bronchial tissue. treat diseases of the respiratory tract. However,
Such effect possibly has a direct participation further studies are needed to better understand
of VOCC, since bronchodilation was not the mechanisms involved, as well as to evaluate
observed with equal potency for the effect of other possible pharmacological and/or electro-
EOLs in contractions evoked by ACh. It can be mechanical pathways. Further studies are also
said that, from a pharmacodynamic point of needed in the area of respiratory physiology to
view, EOLs have a myorelaxant effect, which is show whether studies with swine tissues are
reversible through washing with the nutrient more promising than studies with rat tissues, so
solution, showing that the tissue remained viable
throughout the experiment.

The possible involvement of VOCCs should
be highlighted, since activation of these channels
with membrane depolarization and Ca2+ inflow
through these channels is the major step for the
K+-induced contraction (Somlyo & Somlyo, 1994).

In this regard, previous studies have
reported myorelaxant activity of the species
Lippia alba in aorta, uterus and intestinal portions
of rats (Blanco et al., 2013; Da Silva et al., 2018;
Pereira-De-Morais et al., 2019). Such results
highlight the myorelaxant effect of essential oils
on contractions evoked by K+ and ACh.

The results obtained in this work corroborate
the data found by Carvalho et al. (2018), in which
they demonstrate that the essential oil of L. alba and
its isolated constituents promote full relaxation of
the contractions initiated via electromechanical
excitation-contraction coupling (K+-induced
contraction), in contrast to the low effectiveness
in relaxing the contractions initiated via
pharmacological excitation-contraction coupling
(ACh-induced contraction). Thus, it is suggested
that the observed activity is predominantly related
to the blockade of VOCC.

The works cited for the myorelaxant
effect of a natural product are mostly in muscle
tissue of rodents. The method in the present
study proposes an alternative pharmacological
model for the study of natural substances with
pharmacological potentiality in respiratory
diseases (Dantas et al., 2019).

In this regard, it proposes that this

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Bronchodilator Activity of the essential oil from Lippia sidoides...

as to validate the superiority of the swine tissue oil, thymol, p-cymene, myrcene and caryophyllene
as the state of the art. on rat sciatic nerve excitability. Brazilian Journal of
Medical and Biological Research, v. 50, n. 12, 2017.
CONCLUSION
Blanco, M.A.; Colareda, G.A.; Van Baren, C.; Bandoni,
The results show that EOLs have a myorelaxative A.L.; Ringuelet, J. & Consolini, A.E. Antispasmodic
effect on swine bronchial tissue. This effect is effects and composition of the essential oils from two
likely to be mainly due to blockade of VOCCs, South American chemotypes of Lippia alba. Journal of
since EOLs muscle relaxation showed a greater ethnopharmacology, v. 149, n. 3, p. 803-809, 2013.
pharmacodynamics potency on K+-induced
contraction, which depends largely on the opening Bolton, T.B.; Prestwich, S.A.; Zholos, A.V. &
of these channels. As a result, the potential Gordienko, D.V. Excitation-contraction coupling in
to become a future therapeutic agent in the gastrointestinal and other smooth muscles. Annual
prevention of diseases that affect the respiratory review of physiology, v. 61, n. 1, p. 85-115, 1999.
system, which involve bronco constriction, as in
the case of asthma and bronchitis, became evident. Boskabady, M.H. & Jandaghi, P. Relaxant effects of
We can also observe the effectiveness of the carvacrol on guinea pig tracheal chains and its possible
method chosen for the development of research mechanisms. Die Pharmazie-An International Journal
on respiratory smooth muscle. Further studies will of Pharmaceutical Sciences, v. 58, n. 9, p. 661-663, 2003.
be needed to elucidate the mechanism of action of
EOLs, and to demonstrate whether the method Brito, D.I.V.; Morais-Braga, M.F.B.; Cunha, F.A.B.;
bronchial tissues of pig is better, as related to AlbuquerquE, R.S.; Carneiro, J.N.P.; Lima, M.S.F.
similarity of effect in human respiratory smooth & Lavor, A.K. L.S. Análise fitoquímica e atividade
muscle, than that with rat tissues, the method antifúngica do óleo essencial de folhas de Lippia
already well disseminated, with rat trachea and/ sidoides Cham. e do Timol contra cepas de Candida spp.
or bronchus. This will require direct comparison Rev. Bras. Plantas Med, v. 17, p. 836-844, 2015.
data in swine with human data.
Carvalho, A.F.U.; Melo, V.M.M.; Craveiro, A.A.;
Acknowledgment Machado, M.I.L.; Bantim, M.B. & Rabelo, E.F.
Larvicidal activity of the essential oil from Lippia
This research was funded by Conselho nacional sidoides Cham. against Aedes aegypti Linn. Memórias
de Pesquisa (CNPq) (National Research Council do Instituto Oswaldo Cruz, v. 98, n. 4, p. 569-571, 2003.
(CNPq)), Coordenação de Aperfeiçoamento do
Pessoal de Nível Superior (CAPES) (Coordination Carvalho, P.M.; Macêdo, C.A.; Ribeiro, T.F.; Silva,
for the Improvement of Higher Education A.A.; Da Silva, R.E.; De Morais, L.P. & Barbosa, R.
Personnel - CAPES), Fundação Cearense de Apoio Effect of the Lippia alba (Mill.) NE Brown essential oil
ao Desenvolvimento Científico e tecnológico and its main constituents, citral and limonene, on the
(FUNCAP) (Cearense Foundation for Support tracheal smooth muscle of rats. Biotechnology reports,
for Scientific and Technological Development v. 17, p. 31-34, 2018.
- FUNCAP) and by Ministério da Saúde (the
Ministry of Health (MS). Costa, S.M.O. Constituintes químicos de Lippia sidoides
(Cham.) Verbenaceae. Rev. bras. farmacogn., v.12, p.
Conflict of interests 66-67, 2002.

We confirm that there are no conflicts of interest Craveiro, A.A. Óleos essenciais de plantas do
associated with this publication, and there was Nordeste. Fortaleza, CE: Edições UFC, 1981.
no significant financial support for this work that
could have influenced its outcome. Laranjeira, D.; Carvalho Filho, J.L.S. D.; Souza, P.E.D.;
Blank, A.F.; Alves, P.B.; Jesus, H.C.R.D. & Warwick,
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ANAIS da Academia Cearense de Ciências, v. 4, n. 1, p. 48-52, 2020.
www.aceci.com.br

Artigo Científico/ Scientific Article

The Hormone Melatonin, Diabetes Mellitus, and Alterations
of Nervous System

Klausen Oliveira-Abreu, Ana Carolina Cardoso-Teixeira,
Andrelina Noronha Coelho-de-Souza & José Henrique Leal-Cardoso

Laboratório de Eletrofisiologia - Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará

(Aceito para publicação 09/07/2020)

Author for correspondence: José Henrique Leal-Cardoso, e-mail: [email protected]

Oliveira-Abreu, K.; Cardoso-Teixeira, A.C.; Coelho-de-Souza, A.N. & Leal-Cardoso, J.H. The hormone melatonin,
diabetes mellitus, and alterations of nervous system. ANAIS da Academia Cearense de Ciências. v. 4, n. 1, p.
48-52, 2020.

ABSTRACT
Diabetes mellitus (DM) is a complex metabolic condition, which is clinically characterized by hyperglycemia
caused by a chronic or relative insulin deficiency. Diabetes mellitus is considered a serious health issue, as
it increases the risk of cardiovascular diseases, strokes and microvascular complications. Among the most
prevalent complications one can mention: retinopathy, nephropathy and neuropathy, which are associated
with an increased oxidative stress caused by DM. Several molecules have been studied for the DM treatment,
and the hormone melatonin is one of them. It is mainly synthesized by the pineal gland and has a powerful
antioxidant effect. Studies in humans and in DM experimental models have investigated a relationship between
melatonin and diabetic neuropathy (DN). Melatonin has shown to be a promising molecule in the treatment of
DM and ND, improving aspects such as blood glucose, body mass, oxidative stress, neuroinflammation, nerve
conduction velocity, and neurodegeneration. However, further studies are needed to describe the mechanism of
action of melatonin in DN and to establish standardization in relation to treatment.

Additional keywords: Hyperglycemia; Melatonin; Diabetes mellitus; Diabetic neuropathy.

RESUMO
O Hormônio Melatonina, Diabetes Mellitus e Alterações do Sistema Nervoso
O diabetes mellitus (DM) é uma condição metabólica complexa, que é clinicamente caracterizada por uma
hiperglicemia devido a uma deficiência crônica ou relativa de insulina. O DM é considerado um sério problema
de saúde, pois aumenta o risco de doenças cardiovasculares, acidente vascular encefálico e complicações
microvasculares. Dentre as complicações de maior prevalência se encontram retinopatia, nefropatia e neuropatia,
que são associadas a um aumento no estresse oxidativo causado pelo DM. Várias moléculas têm sido estudadas
para o tratamento do DM, dentre elas o hormônio melatonina. Ela é produzida principalmente pela glândula
pineal e possui um poderoso efeito antioxidante. Estudos em seres humanos e em modelos experimentais de
DM têm investigado a relação entre melatonina e a neuropatia diabética (ND). A melatonina tem se mostrado
uma molécula promissora no tratamento do DM e da ND, melhorando aspectos como glicemia, massa corpórea,
estresse oxidativo, neuroinflamação, velocidade de condução nervosa e neurodegeneração. Entretanto, mais
estudos são necessários para descrever o mecanismo de ação da melatonina na ND e para estabelecer uma
padronização em relação ao tratamento.

Palavras-chave adicionais: Hiperglicemia; Melatonina; Diabetes mellitus; Neuropatia diabética.

INTRODUCTION The DM is characterized as a serious public
health issue, as the disease increases the risk of
Diabetes mellitus (DM) is one of the greatest cardiovascular disease, stroke, and micro vascular
epidemics that the world has faced (Zimmet et al., complications. Among these complications, one
2016). It is a complex metabolic condition, which can mention retinopathy, nephropathy, and
is clinically characterized by hyperglycemia due peripheral neuropathy, which are associated
to a chronic and/or relative insulin deficiency with the increased oxidative stress reported in
(Ashcroft & Rorsman, 2012). DM (Ashcroft & Rorsman, 2012; Mok et al., 2019).

48 ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020.

Oliveira-Abreu, K. et al.

The diabetic neuropathy (DN) is a set of “melatonin” and “diabetic neuropathy” in
clinical syndromes that affect distinct regions Pubmed, one of the most used databases in the
of the nervous system. The DN also has a huge biomedical sciences, resulted in a total of 23
impact on patients’ quality of life mainly by articles, of which 19 were original articles and
causing weakness, ataxia, and incoordination, four were reviews. Among the original articles,
predisposing to falls and fractures. Additionally, 3 were developed with humans and 16 with
DN can results in the loss of thermal, pain, touch, experimental animals.
and vibration perception (Vinik et al., 2013).
The studies that investigated the relationship
There are several compounds already between melatonin and diabetic neuropathy in
described with antioxidant effect, melatonin experimental animals used different species and
(MEL), which is a hormone produced by the pineal experimental models. Another aspect in which
gland, is one of them (Tan et al., 2010). Beside the a large variation was observed was the dose of
antioxidant effect, several studies described the melatonin used in the treatment, the route of
effect of melatonin on the nervous system, for administration and the duration of treatment
example, by inhibiting excitability in neurons of (Table 1).
the peripheral nervous system (PNS) (Oliveira-
Abreu et al., 2018; 2019) or neuroprotective effect 2- Researches with Humans
on disorders that affect the central nervous system In humans, DM has been reported to cause a
(CNS), such as: Parkinson's disease, Alzheimer's, reduction in nocturnal melatonin synthesis, the
and depression (Alghamdi, 2018). period when its synthesis peak (O’Brien et al.,
1986; Tütüncü et al., 2005). Although melatonin
Several studies correlated the effects of MEL, levels reach baseline values during the day, a
the secretion of insulin and glucose homeostasis reduction in the plasma concentration of this
(Sharma et al., 2015; Karamitri & Jockers, 2019). hormone in diabetic patients with autonomic
For example, a reduction in circulating MEL has neuropathy has been reported when compared
been demonstrated in patients with type 2 DM to healthy patients (Tütüncü et al., 2005).
(T2DM) and an increase in the expression of
messenger RNA of melatonin receptors. In diabetic patients with nephropathy, a
sustained adrenergic activity during sleep has
The MEL has also been reported to affect been reported. This parameter is associated
metabolic processes, for example infusion with an increase in noradrenalin levels and it is
of pineal extracts led to hypoglycemia and mentioned that most T2DM patients who have
increased glucose tolerance (Cipolla-Neto et al., nephropathy also have neuropathy, which is
2014). Another important hormone related to associated with a higher risk of death (Nielsen et
metabolism is cortisol and physiological doses of al., 1999).
melatonin inhibit the in vitro ACTH-stimulated
cortisol production. Additionally, melatonin 3- Researches with Experimental Animals
receptors have been demonstrated in the primate 3.1- Effect of Melatonin on Hyperglycemia
adrenal gland, which is responsible for cortisol Diabetes mellitus is clinically characterized by
synthesis (Torres-Farfan et al., 2003). These hyperglycemia due to a chronic and/or relative
data suggest that MEL may improve metabolic insulin deficiency (Ashcroft & Rorsman, 2012).
processes, modulating blood glycemic control, Thus, several studies have investigated the
for example. Also a reduction in the synthesis relationship between melatonin and glycemia in
of this hormone may be associated with the diabetic animals.
development of T2DM (Sharma et al., 2015).
Some studies reported that MEL was able
Thus, this work aims to review melatonin to improve blood glucose (Anwar & Meki, 2003;
and one of the most prevalent complications in Hadjzadeh et al., 2014; Gurel-Gokmen et al., 2018),
DM, diabetic neuropathy. while others reported that MEL had no effect on
this parameter (Baydas et al., 2003; Negi et al.,
RESULTS 2010, 2011; Li et al., 2013; Metwally et al., 2018;
Zhang et al., 2018). Additionally, Ibrahim (2017)
1- General Characterization of Papers reported that the treatment with extract of the
Although melatonin has been extensively leaf of Cucumis melo Var. flexuosus in diabetic
studied in recent years, there are few studies animals induced by STZ caused a reduction in
relating melatonin and diabetic neuropathy. A glycemia and an increase in plasma melatonin,
search conducted in June 2020 with the terms

ANAIS da Academia Cearense de Ciências, v. 4, n. 1, Jan - Jul, 2020. 49