Potential antioxidant & anti-inflammatory protective effect of melatonin receptor agonist in hypo & hyperthyroid rat model

Authors

  • Radwa M. Alsayed Department of Pharmacology, Faculty of Medicine -Zagazig University , (2) Department of Physiology, Faculty of Medicine -Zagazig University, Egypt, (3) Department of Physiology, Faculty of Medicine -Benha University and (4) M.B.B.CH, Faculty of MedicineSirt University–Lybia Author
  • Yassmen M. El-sayed Department of Pharmacology, Faculty of Medicine -Zagazig University , (2) Department of Physiology, Faculty of Medicine -Zagazig University, Egypt, (3) Department of Physiology, Faculty of Medicine -Benha University and (4) M.B.B.CH, Faculty of MedicineSirt University–Lybia Author
  • Mona K. Alawam Department of Pharmacology, Faculty of Medicine -Zagazig University , (2) Department of Physiology, Faculty of Medicine -Zagazig University, Egypt, (3) Department of Physiology, Faculty of Medicine -Benha University and (4) M.B.B.CH, Faculty of MedicineSirt University–Lybia Author
  • Areej Omar Ramadhan Abdullah Department of Pharmacology, Faculty of Medicine -Zagazig University , (2) Department of Physiology, Faculty of Medicine -Zagazig University, Egypt, (3) Department of Physiology, Faculty of Medicine -Benha University and (4) M.B.B.CH, Faculty of MedicineSirt University–Lybia Author
  • Eman Abdel Raouf Mohamed Department of Pharmacology, Faculty of Medicine -Zagazig University , (2) Department of Physiology, Faculty of Medicine -Zagazig University, Egypt, (3) Department of Physiology, Faculty of Medicine -Benha University and (4) M.B.B.CH, Faculty of MedicineSirt University–Lybia Author

DOI:

https://doi.org/10.48047/bdtybn11

Keywords:

Ramelteon; oxidative stress; thyroid disorders

Abstract

 Background: Hormonal instability is linked to inflammation and oxidative stress (OS) through common pathways. Thyroid hormones have been found to play a major part in the antioxidant balance among many hormonal factors, since OS has been linked to both hypothyroidism and hyperthyroidism in humans and animals. A number of research studies have demonstrated the antioxidant, antiinflammatory, and protective properties of melatonin receptor agonist Ramelteon (RML). Accordingly, the aim of the current study was to examine the potential antioxidant and anti-inflammatory properties of RML on OS induced by thyroid dysfunction (hyperthyroidism, hypothyroidism) in a rat model

 

Methods: Thirty adult albino male rats (fed ordinary laboratory diet along the four weeks’ study), were randomly divided into 5 groups; control group, experimentally-induced hypothyroid group (rats received a single dose of 2 mg carbimazole/100g daily diluted in drinking water by oral gavage for four weeks), hypothyroid group with administration of RML (10 mg/kg/day diluted in drinking water, via oral gavage for four weeks), experimentally- induced hyperthyroid group (rats received a single daily dose of 2μg/ml L-thyroxin diluted in drinking water by oral gavage for four weeks) and hyperthyroid group with administration of RML (10 mg/kg/day diluted in drinking water, via oral gavage for four weeks). All rats' body mass indices (BMIs) were assessed at the end of the experiment. Results: The final BMI index, serum glucose, insulin, HOMA-IR, serum T3, serum T4, serum TSH, serum total cholesterol, serum triglycerides, serum low density lipoprotein, serum tumor necrosis factor alpha (TNF-α), serum interleukin-6 (IL-6), and serum oxidative stress markers, such as serum malondialdehyde (MDA) and reduced glutathione (GSH), superoxide dismutase (SOD), were found to differ statistically significantly between the hypothyroid and hyperthyroid groups. In terms of final BMI index, serum glucose, insulin, HOMA-IR, total cholesterol, triglycerides, low density lipoprotein, serum IL-6, TNF-α, and serum oxidative stress markers (MDA), (GSH), and (SOD), ramelteon significantly reduced these levels. This suggests that ramelteon has anti-inflammatory and antioxidant properties in thyroid dysfunction (hyperthyroidism, hypothyroidism). Conclusions: Ramelteon may be able to diminish the oxidative and metabolic damage caused by hypo- and hyperthyroidism. Its protective anti-obesity, hypoglycemic, hypolipidemic, antioxidant and anti-inflammatory properties may contribute to its useful effects 

Downloads

Download data is not yet available.

References

- Rashmi Mullur, Yan-Yun Liu, and Gregory A. Brent(2014)Thyroid Hormone

Regulation of Metabolism. Physiol Rev. Apr; 94(2): 355–382.

- Zs-Nagy I(2001). On the true role of oxygen free radicals in the living state, aging, and

degenerative disorders. Annals of the New York Academy of Sciences. 2001;928:187–199

- Lenaz G(1998). Role of mitochondria in oxidative stress and ageing. Biochimica et Biophysica

Acta. 1366(1-2):53–67

- Villanueva, C. Alva-Sánchez, and J. Pacheco-Rosado(2013). The Role of Thyroid Hormones

as Inductors of Oxidative Stress and Neurodegeneration. Oxid Med Cell Longev. 218145.

-Asayama K, Dobashi K, Hayashibe H, Megata Y, Kato K. (1987) Lipid peroxidation and free

radical scavengers in thyroid dysfunction in the rat: a possible mechanism of injury to heart and

skeletal muscle in hyperthyroidism. Endocrinology. 121(6):2112–2118.

- Araujo ASDR, De Miranda MFS, De Oliveira U, et al. (2010) Increased resistance to hydrogen

peroxide-induced cardiac contracture is associated with decreased myocardial oxidative stress in

hypothyroid rats. Cell Biochemistry and Function. ;28(1):38–44.

-.Wu G-C, Peng C-K, Liao W-I, Pao H-P, Huang K-L, Chu S-J(2020). Melatonin receptor

agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10

production. Respir Res. 21:1–17.

- Wu X-L, Lu S-S, Liu M-R, Tang W-D, Chen J-Z, Zheng Y-R, et al (2020). Melatonin receptor

agonist ramelteon attenuates mouse acute and chronic ischemic brain injury. Acta Pharmacol

Sinica. 41:1016–24.

- Zaidi T, Khan A, Hasan B and Faruqi A(2004) Carbimazole induced thyroid histopathy in

albino rats during development. J. anat. Soc.53 (2): 14 – 17

-Rahime Aslankoc, Mehtap Savran, Duygu Kumbul Doğuç, Murat Sevimli, Hale Tekin, and

Mine Kaynak(2022). Ameliorating effects of ramelteon on oxidative stress, inflammation,

apoptosis, and autophagy markers in methotrexate-induced cerebral toxicity. Iran J Basic Med

Sci. Oct; 25(10): 1183–1189.

- Serakides R, Ocarino N, Cardoso T, Moraes J, Nunes V and Silva A. (2005)Resposta da

paratireóide de ratas às variações do cálcio e fósforo plasmáticos no hipertireoidismo e

hipogonadismo. Arquivo Brasileiro de Medicina Veterinária e Zootecnia; 57: 48-54.

- Novelli E, Diniz Y, Galhardi C, Ebaid G, Rodrigues H, Mani F, et al. (2007)

Anthropometrical parameters and markers of obesity in rats. Laboratory animals; 41(1): 111-119.

- Suman R, Ray Mohanty I, Borde M, Maheshwari U and Deshmukh Y. (2016) Development

of an Experimental Model of Diabetes Co- Existing with Metabolic Syndrome in Rats. Advances

in Pharmacological Sciences: 11.

- Sun G, Bishop J, Khalili S, Vasdev S, Gill V, Pace D et al.(2007) Serum visfatin

concentrations are positively correlated with serum triacylglycerols and down-regulated by

overfeeding in healthy young men. The American journal of clinical nutrition; 85(2): 399-404

- Friedewald W, Levy R and Fredrickson D.(1972) Estimation of the concentration of lowdensity lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical

chemistry; 18(6): 499-502.

- Yeldu M and Ishaq S. (2017): Changes in lipid peroxidation, free radical scavengers and

tumour necrosis factor-alpha in serum of wistar rats with induced thyroid dysfunction. Annual

Research & Review in Biology; 19(3):1-14.

- Venditti P, Napolitano G, Barone D, Coppola I and Di Meo S (2015). Effect of thyroid state

on enzymatic and non-enzymatic processes in H2O2 removal by liver mitochondria of male rats.

Molecular and cellular endocrinology; 403: 57-63.

- Kim M and Lee B (2019): Therapeutic Effect of Scutellaria baicalensis on LThyroxineInduced Hyperthyroidism Rats. Evid Based Complement Alternat Med; 2019:3239649

- de Vries E, Van Beeren H, Ackermans M, Kalsbeek A, Fliers E and Boelen, A.(2015):

Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male

rats. Journal of Endocrinology; 224 (1): 25-35.

- Vazquez-Anaya G, Martinez B, Soñanez- Organis J, Nakano D, Nishiyama A and Ortiz R

(2017): Exogenous thyroxine improves glucose intolerance in insulin-resistant rats. Journal of

Endocrinology; 232 (3): 501-511.

- Ormazabal V, Nair S, Elfeky O, Aguayo C, Salomon C & Zuñiga F (2018): Association

between insulin resistance and the development of cardiovascular disease. Cardiovascular

diabetology; 17(1): 1-14.

-Tetsuji Tsunoda, Masayo Yamada, Tomoaki Akiyama, Taichi Minami, Taishi Yoshii,

Yoshinobu Kondo, Shinobu Satoh,c and Yasuo Terauchi (2016): The Effects of Ramelteon on

Glucose Metabolism and Sleep Quality in Type 2 Diabetic Patients With Insomnia: A Pilot

Prospective Randomized Controlled Trial J Clin Med Res. 8(12): 878–887.

-She M, Hou H, Wang Z, Zhang C, Laudon M, Yin W. (2014) Melatonin rescues 3T3-L1

adipocytes from FFA-induced insulin resistance by inhibiting phosphorylation of IRS-1 on

Ser307. Biochimie. ;103:126–130. doi: 10.1016/j.biochi.2014.05.001.

- She M, Laudon M, Yin W. (2014) Melatonin receptors in diabetes: a potential new

therapeutical target? Eur J Pharmacol. ;744:220–223. doi: 10.1016/j.ejphar.2014.08.012.

- Agil A, Rosado I, Ruiz R, Figueroa A, Zen N, Fernandez-Vazquez G. (2012) Melatonin

improves glucose homeostasis in young Zucker diabetic fatty rats. J Pineal Res. ;52(2):203–210.

doi: 10.1111/j.1600-079X.2011.00928.x.

- Hussain SA, Khadim HM, Khalaf BH, Ismail SH, Hussein KI, Sahib AS (2006). Effects of

melatonin and zinc on glycemic control in type 2 diabetic patients poorly controlled with

metformin. Saudi Med J. 27(10):1483–1488

- Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N.( 2011) Efficacy and

safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, doubleblind, crossover study. Diabetes Metab Syndr Obes. 4:307–313. –

-Ayako Uchinaka, Yuri Kawashima, Yuki Sano, Shogo Ito, Yusuke Sano, Kai Nagasawa,

Natsumi Matsuura, Mamoru Yoneda, Yuichiro Yamada, Toyoaki Murohara, Kohzo

Nagata(2018) Effects of ramelteon on cardiac injury and adipose tissue pathology in rats with

metabolic syndrome Annals of the New York Academy of SciencesVolume 1421, Issue 1 p. 73-

- Oktay S, Uslu L and Emekli N (2017): Effects of altered thyroid states on oxidative stress

parameters in rats. J Basic Clin Physiol Pharmacol; 28 (2):159–65.

-Christina P.C. Borba, Xiaoduo Fan, Paul M. Copeland, M.D., Alexander Paiva, MA, Oliver

Freudenreich, and David C. Henderson,(2011). Placebo-controlled pilot study of ramelteon for

adiposity and lipids in patients with schizophrenia J Clin Psychopharmacol. 2011 Oct; 31(5):

–658

- Najafi Z, Zarban A, Chamani E, Honarbakhsh M and Sharifzadeh G (2020): Comparison of

Biochemical and Oxidative Stress Parameters in Hypo and Hyperthyroid Rat Models. Modern

Care Journal; 17(3): e102444.

- Minakhina S, De Oliveira V, Kim S, Zheng H and Wondisford F (2021): Thyroid hormone

receptor phosphorylation regulates acute fasting- induced suppression of the hypothalamic–

pituitary–thyroid axis. Proceedings of the National Academy of Sciences; 118(39):

e2107943118.

- Erdamar H, Demirci H, Yaman H, Erbil M, Yakar T, Sancak B et al. (2008): The effect of

hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and

antioxidant status. Clin Chem Lab Med; 46(7): 1004-1010.

- Cheserek M, Wu G, Ntazinda A, Shi Y, Shen L and Le G (2015): Association between thyroid

hormones, lipids and oxidative stress markers in subclinical hypothyroidism. Journal of medical

Biochemistry; 34(3): 323-331.

- Geng-Chin Wu, Chung-Kan Peng, Wen-I Liao,Hsin-Ping Pao,Kun-Lun Huang, and Shi-Jye

Chu 2020 Melatonin receptor agonist protects against acute lung injury induced by ventilator

through up-regulation of IL-10 production. Respir Res. ; 21: 65.

- Pan X, Zhu L, Lu H, Wang D, Lu Q, Yan H. 2015 Melatonin attenuates oxidative damage

induced by acrylamide in vitro and in vivo. Oxidative Med Cell Longev. ;2015:703709. doi:

1155/2015/703709.

- Wang ML, Wei CH, Wang WD, Wang JS, Zhang J, Wang JJ. Melatonin attenuates lung

ischaemia-reperfusion injury via inhibition of oxidative stress and inflammation. Interact

Cardiovasc Thorac Surg. 2018;26:761–767.

-Russel J Reiter , Dun-Xian Tan, Juan C Mayo, Rosa M Sainz, Josefa Leon, Zbigniew

Czarnocki .(2003)Melatonin as an antioxidant: biochemical mechanisms and pathophysiological

implications in humans. Acta Biochim Pol;50(4):1129-46.

-Baldissarelli J, Mânica A, Pillat M, Bagatini M, Leal D, Abdalla F et al. (2020): Increased

cytokines production and oxidative stress are related with purinergic signaling and cell survival

in post-thyroidectomy hypothyroidism. Molecular and cellular endocrinology; 499: 110594.

- Zhou J, Cheng G, Pang H, Liu Q and Liu Y (2018): The effect of 131I-induced

hypothyroidism on the levels of nitric oxide (NO), interleukin 6 (IL-6), tumor necrosis factor

alpha (TNF-α), total nitric oxide synthase (NOS) activity, and expression of NOS isoforms in

rats. Bosnian journal of basic medical sciences; 18(4): 305.- 3012.

- Lu Y, Yeh W and Ohashi P (2008): LPS/TLR4 signal transduction pathway. Cytokine; 42(2):

-151.

- Marfella R, Ferraraccio F, Rizzo M, Portoghese M, Barbieri M, Basilio C et al. (2011): Innate

immune activity in plaque of patients with untreated and L-thyroxine-treated subclinical

hypothyroidism. J Clin Endocrinol Metab; 96(4): 1015-1020.

- Reza Jouybar , Mahtab Setoodeh , Zeinabsadat Fattahi Saravi , Sedigheh Ahmadi , Ali

Karami , Saeed Khademi , Ahad Izadpanah , Mansour Jannati , Masih Shafa , Elham

Asadpour , Farzaneh Masih , Mahyar Malekzadeh ( 2020) The Effect of Melatonin on the

Serum Level of Interleukin 6 and Interleukin 9 in Coronary Artery Bypass Grafting Surgery .

Asian J Anesthesiol Mar 1;58(1):35-44

- Chen D, Li Z, Bao P, et al. (2019) Nrf2 deficiency aggravates angiotensin II-induced cardiac

injury by increasing hypertrophy and enhancing IL-6/STAT3-dependent inflammation.Biochim

Biophys Acta Mol Basis Dis. 1865(6):1253–1264.

-Nioi, P, McMahon, M, Itoh, K., Yamamoto, M., Hayes, J.D (2003) Identification of a novel

Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone

oxidoreductase 1 gene: Reassessment of the ARE consensus sequence. Biochem. J. 2003, 374,

–348.

-Yu GM, Kubota H, Okita M, Maeda T. (2017) The anti-inflammatory and antioxidant effects

of melatonin on LPS-stimulated bovine mammary epithelial cells. PLoS One.;12(5):e0178525.

-Xia MZ, Liang YL, Wang H, Chen X, Huang YY, Zhang ZH, et al.( 2012) Melatonin

modulates TLR4-mediated inflammatory genes through MyD88- and TRIFdependent signaling

pathways in lipopolysaccharidestimulated RAW264.7 cells. J Pineal Res.

;53(4):325-34.

-Ahmad SF, Ansari MA, Zoheir KM, Bakheet SA, Korashy HM, Nadeem A, et al. (2015)

Regulation of TNFalphaand NF-kappaB activation through the JAK/STAT signaling pathway

downstream of histamine4 receptor in a rat model of LPS-induced joint inflammation.

Immunobiology.;220(7):889-98.

-Celinski K, Konturek PC, Slomka M, Cichoz-Lach H, Brzozowski T, Konturek SJ, et al

(2014). Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat

metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease--14

months follow up. J Physiol Pharmacol.;65(1):75-82.

-Usta Sofu G, Erzurumlu Y, Karaca U, Candan IA, Savran M, Asci H, et al.( 2022) Melatonin

receptor agonist ramelteon alleviates experimental acute ocular inflammation via HIF-

Alpha/VEGF/E-NOS signaling. Eur J Ophthalmol.:11206721221123878.

-Aslankoc R, Savran M, Doguc DK, Sevimli M, Tekin H, Kaynak M.( 2022) Ameliorating

effects of ramelteon on oxidative stress, inflammation, apoptosis, and autophagy markers in

methotrexate-induced cerebral toxicity. Iran J Basic Med Sci.;25(10):1183-9

-.Wang T, Li Z, Xia S, Xu Z, Chen X, Sun H.(2021) The Protective Effects of Ramelteon

Against Isoflurane- Induced Insults and Inflammatory Response in Brain Microvascular

Endothelial Cells. Neurotox Res.;39(3):677-86.

-Yang S, Wang J, Wang D, Guo L, Yu D. (2021) Melatonin Receptor Agonist Ramelteon

Suppresses LPS-Induced Neuroinflammation in Astrocytes. ACS Chem Neurosci;12(9):1498-

Downloads

Published

2023-01-04

How to Cite

Potential antioxidant & anti-inflammatory protective effect of melatonin receptor agonist in hypo & hyperthyroid rat model (R. M. Alsayed, Y. M. El-sayed, M. K. Alawam, A. O. Ramadhan Abdullah, & E. A. Raouf Mohamed , Trans.). (2023). Cuestiones De Fisioterapia, 52(1), 118-130. https://doi.org/10.48047/bdtybn11