Metimazol ile Oluşturulan Sıçan Hipotiroidi Modelinde Kognitif Fonksiyonlar, Anksiyete ve Depresyon Benzeri Davranışların Değerlendirilmesi: Pilot Çalışma

Yıl 2022, Cilt: 48 Sayı: 2, 147 - 153, 15.09.2022

Oğuzhan Ekin Efe Selda Emre Aydıngöz Karl Michael Lux Eda Özer Ayşegül Süzer Meral Tuncer

https://doi.org/10.32708/uutfd.1081090

Öz

Hipertiroidizm tedavisinde yaygın olarak kullanılan metimazol, deneysel çalışmalarda geçici hipotiroidizm modeli oluşturmak için kullanılmaktadır. Çalışmamızda metimazol ile oluşturulan sıçan hipotiroidi modelinde kognitif fonksiyonların değerlendirilmesi ve hipotiroidinin anksiyete ve depresyon benzeri davranışlar üzerine etkisinin belirlenmesi amaçlanmıştır. Oniki adet erişkin dişi/erkek Wistar sıçan (250-300 g) iki gruba ayrılarak bir gruba 4 hafta süre ile içme suyu içinde %0,02 metimazol verilerek hipotiroidizm oluşturulmuş, diğer gruba normal içme suyu verilmiştir. Dört hafta sonunda, Morris su labirenti, yükseltilmiş artı labirent, kuyruk suspansiyon testi, pasif sakınma testi uygulanmıştır. Metimazol kesildikten 8 hafta sonra serum serbest T4 ve TSH düzeyleri ölçülmüş ve tiroid dokusu histopatolojik olarak değerlendirilmiştir. Morris su labirenti testinde sadece 1. günde gruplar arasında anlamlı fark izlenmiştir (p < 0,001). Pasif sakınma testinde ise gruplar arasında anlamlı fark görülmemiştir (p = 0,477). Yükseltilmiş artı labirentte hipotiroid sıçanlar açık alanda daha fazla süre geçirmiş (123,5 ± 35,5 sn vs. 12,5 ± 7,9 sn; p = 0,012); açık ve orta alana daha fazla sayıda giriş yapmıştır (sırasıyla, 3,0 ± 0,4 vs. 0,7 ± 0,5; p = 0,006, 6,2 ± 1,2 vs. 2,8 ± 0,7; p = 0,042). Kuyruk suspansiyon testinde hipotiroid grubun hareketsiz kaldığı süre, ötiroid gruba göre anlamlı olarak daha uzun bulunmuştur (186,2 ± 19,5 sn vs. 110,3 ± 26,2 sn; p = 0,043). Histopatolojik incelemede, hipotiroid grubunda kolloid vakuolizasyonu izlenmiş, ancak serum serbest T4 ve TSH düzeylerinde gruplar arasında fark görülmemiştir. Sonuç olarak, sıçanda metimazol hipotiroidi modeli öğrenme ve bellekte bozulma oluşturmaksızın, anksiyeteyi azaltıp depresyona eğilimi artırmaktadır. Bu zeminde, hipotiroidi ve kognitif fonksiyon ilişkisini aydınlatmaya yönelik ileri çalışmalar planlanmalıdır.

Anahtar Kelimeler

Hipotiroidizm, Kognitif fonksiyon, Sıçan, Metimazol

Destekleyen Kurum

Başkent Üniversitesi

Proje Numarası

DA 21/04

Teşekkür

Başkent Üniversitesi Tıp Fakültesi Histoloji ve Embriyoloji Anabilim Dalı'ndan Arş. Gör. Ekin EFE'ye ve Tıbbi Biyokimya Anabilim Dalı'ndan Sinan KARAÇOCUK'a çalışmadaki yardımları için teşekkürlerimizi sunarız.

Evaluation of Cognitive Functions, Anxiety- and Depression-Like Behaviours in Methimazole-Induced Rat Hypothyroidism Model: A Pilot Study

Öz

Methimazole, a widely used agent in the treatment of hyperthyroidism, is also used to induce hypothyroidism in experimental studies. In this study, we aimed to evaluate cognitive functions and anxiety- and depression-like behaviours in a methimazole-induced rat hypothyroidism model. Twelve adult female/male Wistar rats (250-300 g) were randomly divided into two groups, one of which was given 0.02% methimazole in drinking water for 4 weeks, as the other group was given normal water. After 4 weeks, Morris water maze, elevated plus maze, tail suspension test, passive avoidance test was applied. Serum free T4 and TSH levels were measured 8 weeks after discontinuation of methimazole, and thyroid tissue was evaluated histopathologically. In the Morris water maze test, a significant difference was observed between the groups only on the 1st day (p < 0.001). There was no significant difference between the groups in the passive avoidance test (p = 0.477). In the elevated plus maze, hypothyroid rats spent more time in the open-field (123.5 ± 35.5 sec vs. 12.5 ± 7.9 sec; p = 0.012); made more entries into the open and middle area (3.0 ± 0.4 vs. 0.7 ± 0.5; p = 0.006 and 6.2 ± 1.2 vs. 2.8 ± 0.7; p = 0.042, respectively). In the tail suspension test, the duration of immobility was significantly longer in the hypothyroid group (186.2 ± 19.5 sec vs. 110.3 ± 26.2 sec; p = 0.043). In the histopathological examination, colloid vacuolization was observed in the hypothyroid group, but serum free T4 and TSH levels did not show difference between the groups. In conclusion, methimazole-induced hypothyroidism decreases anxiety and increases tendency to depression without impairing learning and memory. On this basis, further studies should be planned to elucidate the relationship between hypothyroidism and cognitive functions.

Anahtar Kelimeler

Hypothyroidism, Cognitive Function, Rat, Methimazole

Proje Numarası

DA 21/04

Kaynakça

• 1.Vallortigara J, Alfos S, Micheau J et al. T3 administration in adult hypothyroid mice modulates expression of proteins involved in striatal synaptic plasticity and improves motorbehavior. Neurobiol Dis. 2008;31(3):378-85.
• 2.Boelaert K, Franklyn JA. Thyroid hormone in health anddisease. J Endocrinol. 2005;187(1):1-15.
• 3.Constant EL, Adam S, Seron X, et al. Anxiety and depression, attention, and executive functions in hypothyroidism. J Int Neuropsychol Soc. 2005;11(5):535-44.
• 4.Gulseren S, Gulseren L, Hekimsoy Z, et al. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res. 2006;37(1):133-9.
• 5.Miller KJ, Parsons TD, Whybrow PC, van Herle K, Rasgon N,van Herle A, Martinez D, Silverman DH, Bauer M. Memory improvement with treatment of hypothyroidism. Int J Neurosci. 2006;116(8):895-906.
• 6.Oziol L, Faure P, Bertrand N, et al. Inhibition of in vitro macrophage-induced low density lipoprotein oxidation by thyroid compounds. J Endocrinol. 2003;177(1):137-46.
• 7.Torun AN, Kulaksizoglu S, Kulaksizoglu M, et al. Serum total antioxidant status and lipid peroxidation markermalondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf). 2009;70(3):469-74.
• 8.Psarra AM, Solakidi S, Sekeris CE. The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors inmitochondria of animal cells. Mol Cell Endocrinol. 2006;246(1-2):21-33.
• 9.Rahaman SO, Ghosh S, Mohanakumar KP, et al.Hypothyroidism in the developing rat brain is associated with marked oxidative stress and aberrant intraneuronal accumulation of neurofilaments. Neurosci Res. 2001;40(3):273-9.
• 10.Pérez-Severiano F, Escalante B, Vergara P, Ríos C, Segovia J. Age-dependent changes in nitric oxide synthase activity andprotein expression in striata of mice transgenic for the Huntington's disease mutation. Brain Res. 2002;951(1):36-42.
• 11.Işman CA, Yeğen BC, Alican I. Methimazole-inducedhypothyroidism in rats ameliorates oxidative injury in experimental colitis. J Endocrinol. 2003;177(3):471-6.
• 12.Hayat NQ, Tahir M, Munir B, et al. Effect of methimazole-induced hypothyroidism on histological characteristics of parotid gland of albino rat. J Ayub Med Coll Abbottabad. 2010;22(3):22-7.
• 13.Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA,Vaidya VA. Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci.2005;29(3):414-26.
• 14.Cortés C, Eugenin E, Aliaga E, et al. Hypothyroidism in theadult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density. Thyroid. 2012;22(9):951-63.
• 15.Salas-Lucia F, Pacheco-Torres J, González-Granero S, García-Verdugo JM, Berbel P. Transient hypothyroidism during lactation alters the development of the corpus callosum in rats. an in vivo magnetic resonance ımage and electron microscopy study. Front Neuroanat. 2020;14:33.
• 16.Mishra J, Vishwakarma J, Malik R, et al. Hypothyroidism induces ınterleukin-1-dependent autophagy mechanism as a key mediator of hippocampal neuronal apoptosis and cognitive decline in postnatal rats. Mol Neurobiol. 2021;58(3):1196-211.
• 17.O'Hare E, Kim EM, Page D, Reid R. Effects of thyroxinetreatment on histology and behavior using the methimazolemodel of congenital hypothyroidism in the rat. Neuroscience. 2015;285:128-38.
• 18.Nunez J. Morris water maze experiment. J Vis Exp. 2008;(19):897.
• 19.Komada M, Takao K, Miyakawa T. Elevated plus maze formice. J Vis Exp. 2008;(22):1088.
• 20.Steru L, Chermat R, Thierry B, et al. The tail suspension test: anew method for screening antidepressants in mice. Psychopharmacology (Berl). 1985;85(3):367-70.
• 21.Rodriguez A, Zhang H, Klaminder J, et al. ToxTrac: a fast and robust software for tracking organisms. Met Ecol Evol. 2018;9:460-4.
• 22.Zhou XL, Han Y, Mail WJ, Liu J, Wang H, Feng L, Gao L,Zhao JJ. Different doses and Rroutes of administration of methimazole affect thyroid status in methimazole-induced hypothyroidism in rats. West Indian Med J. 2015;7:65(1):93-97.
• 23.Cakic-Milosevic M, Korac A, Davidovic V. Methimazole-induced hypothyroidism in rats: Effects on body weight and histological characteristics of thyroid gland. Jugoslovenska Medicinska Biohemija. 2004; 23: 143-147.
• 24.Hosseini M, Dastghaib SS, Rafatpanah H, Hadjzadeh MA, Nahrevanian H, Farrokhi I. Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth. Clinics (Sao Paulo).2010;65(11):1175-81.
• 25.van Wijk N, Rijntjes E, van de Heijning BJ. Perinatal and chronic hypothyroidism impair behavioural development inmale and female rats. Exp Physiol. 2008;93(11):1199-209.
• 26.Xu YX, Sun Y, Cheng J, et al. Genetic difference of hypothyroidism-ınduced cognitive dysfunction in C57BL/6j and 129/Sv mice. Neurochem Res. 2019;44(8):1999-2006.
• 27.Chaalal A, Poirier R, Blum D, et al. PTU-induced hypothyroidism in rats leads to several early neuropathological signs of Alzheimer's disease in the hippocampus and spatial memory impairments. Hippocampus. 2014;24(11):1381-93.
• 28.Yu D, Zhou H, Yang Y, et al. The bidirectional effects ofhypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats. Horm Behav. 2015;69:106-15.
• 29.Jin Z, Ling J, Yu J, He M, Ni P, Zhang F, Wang Y. Serotonin2A receptor function and depression-like behavior in rats model of hypothyroidism. Exp Brain Res. 2021;239(8):2435-444.
• 30.Lee J, Yi S, Kang YE, et al. Morphological and functional changes in the thyroid follicles of the aged murine and humans. J Pathol Transl Med. 2016;50(6):426-35.
• 31.Gérard AC, Denef JF, Colin IM, van den Hove MF. Evidencefor processing of compact insoluble thyroglobulin globules in relation with follicular cell functional activity in the human and the mouse thyroid. Eur J Endocrinol. 2004;150(1):73-80.