Treadmill exercise improves neuronal survival by inhibiting apoptosis in the prefrontal cortex of congenital hypothyroid rats

authors:

avatar sakineh shafia , avatar Moslem Mohammadi , *

Koomesh: Vol.25, issue 4; 452-459
published online: October 01, 2023
article type: Research Article
received: July 02, 2023
accepted: September 01, 2023

how to cite: shafia S, Mohammadi M. Treadmill exercise improves neuronal survival by inhibiting apoptosis in the prefrontal cortex of congenital hypothyroid rats. koomesh. 2023;25(4):e152843. 

Abstract

Introduction: Thyroid hormone deficiency during development can have detrimental effects on the structure and function of the nervous system. This study aimed to examine the effects of developmental thyroid hormone deficiency on neuronal survival and gene expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 in the prefrontal cortex of congenital hypothyroid rats. The possible protective role of treadmill exercise was also investigated. Materials and Methods: A congenital hypothyroid model was made by treatment of pregnant Wistar rats with propylthiouracil (PTU) in drinking water from the sixth day of gestation until the end of the lactation period. Control mothers received water during this period. The male offspring were then divided into two groups with/without four weeks of treadmill exercise. Next, the animals were sacrificed and prefrontal cortices were isolated to examine neuronal survival and expression of apoptosis-related genes (Bax and Bcl-2) using cresyl violet staining and real-time polymerase chain reaction, respectively. Results: Our results demonstrated that decreased neuronal survival was associated with a significant increase in Bax and a significant decrease in Bcl-2 gene expression in congenital hypothyroid rats. Treadmill exercise was able to increase the number of surviving neurons by decreasing Bax and increasing Bcl-2 levels; however, significant differences still remained compared to the control group. Conclusion: Developmental thyroid hormone deficiency leads to neuronal damage by activating the apoptosis mechanism. Exercise can improve neuronal survival by inhibiting apoptosis in the prefrontal cortex of congenital hypothyroid rats.

References

  • 1.

    Anyetei-Anum CS, Roggero VR, Allison LA. Thyroid hormone receptor localization in target tissues. J Endocrinol 2018; 237: R19-R34.

  • 2.

    Cherella CE, Wassner AJ. Update on congenital hypothyroidism. Curr Opin Endocrinol Diabetes Obes 2020; 27: 63-69.

  • 3.

    Ghaffari Z, Vafaei AA, L. R-PA, Hadjzadeh MAR, Hosseini SM. Effects of maternal hypothroidism during preganacy on anxiety-like behaviors in adulthood rats: Impact of moderate treadmill exercise. Koomesh 2016; 17: 707-717. (Persian).

  • 4.

    Morte B, Dez D, Aus E, Belinchn MM, Gil-Ibez P, Grijota-Martnez C, Navarro D, de Escobar GM, Berbel P, Bernal J. Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. Endocrinology 2010; 151: 810-820.

  • 5.

    Sui L, Anderson WL, Gilbert ME. Impairment in short-term but enhanced long-term synaptic potentiation and ERK activation in adult hippocampal area CA1 following developmental thyroid hormone insufficiency. Toxicol Sci 2005; 85: 647-656.

  • 6.

    Rovet JF, Ehrlich R. Psychoeducational outcome in children with early-treated congenital hypothyroidism. Pediatrics 2000; 105: 515-522.

  • 7.

    Zhang L, Blomgren K, Kuhn HG, Cooper-Kuhn CM. Effects of postnatal thyroid hormone deficiency on neurogenesis in the juvenile and adult rat. Neurobiol Dis 2009; 34: 366-374.

  • 8.

    Brady J, Cannupp A, Myers J, Jnah AJ. Congenital Hypothyroidism. Neonatal Netw 2021; 40: 377-385.

  • 9.

    Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010; 5: 17.

  • 10.

    Peters C, van Trotsenburg ASP, Schoenmakers N. Diagnosis of endocrine disease: Congenital hypothyroidism: update and perspectives. Eur J Endocrinol 2018; 179: R297-R317.

  • 11.

    Andersen SL, Knsgaard L, Olsen J, Vestergaard P, Andersen S. Maternal thyroid function, use of antithyroid drugs in early pregnancy, and birth defects. J Clin Endocrinol Metab 2019; 104: 6040-6048.

  • 12.

    Gong J, Dong J, Wang Y, Xu H, Wei W, Zhong J, Liu W, Xi Q, Chen J. Developmental iodine deficiency and hypothyroidism impair neural development, up-regulate caveolin-1 and down-regulate synaptophysin in rat hippocampus. J Neuroendocrinol 2010; 22: 129-139.

  • 13.

    Malhi H, Guicciardi ME, Gores GJ. Hepatocyte death: a clear and present danger. Physiol Rev 2010; 90: 1165-1194.

  • 14.

    Martinvalet D, Zhu P, Lieberman J. Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity 2005; 22: 355-370.

  • 15.

    Leber B, Lin J, Andrews DW. Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 2007; 12: 897-911.

  • 16.

    Zare Z, Zarbakhsh S, Tehrani M, Mohammadi M. Paraoxon-induced damage in rat hippocampus is associated with alterations in the expression of apoptosis-related proteins. Pestic Biochem Physiol 2020; 166: 104580.

  • 17.

    Braganhol E, Bruno AN, Bavaresco L, Barreto-Chaves ML, Sarkis JJ, Battastini AM. Neonatal hypothyroidism affects the adenine nucleotides metabolism in astrocyte cultures from rat brain. Neurochem Res 2006; 31: 449-454.

  • 18.

    Cesur G, Eren MK, Eren E, Ergin K, Ek RO, Yldz Y, et al. Effect of experimentally induced hypothyroidism during gestation period on activity dependent neurotrophic factor (ADNF) in newborn rat brain tissue. Horm Mol Biol Clin Investig 2018; 36.

  • 19.

    Mohan V, Sinha RA, Pathak A, Rastogi L, Kumar P, Pal A, Godbole MM. Maternal thyroid hormone deficiency affects the fetal neocorticogenesis by reducing the proliferating pool, rate of neurogenesis and indirect neurogenesis. Exp Neurol 2012; 237: 477-488.

  • 20.

    Xing Q, Shan Z, Gao Y, Mao J, Liu X, Yu J, et al. Differential expression of MicroRNAs and miR-206-mediated downregulation of BDNF expression in the rat fetal brain following maternal hypothyroidism. Horm Metab Res 2018; 50: 696-703.

  • 21.

    Ylli D, Wartofsky L. Can we link thyroid status, energy expenditure, and body composition to management of subclinical thyroid dysfunction? J Clin Endocrinol Metab 2019; 104: 209-212.

  • 22.

    Altaye KZ, Mondal S, Legesse K, Abdulkedir M. Effects of aerobic exercise on thyroid hormonal change responses among adolescents with intellectual disabilities. BMJ Open Sport Exerc Med 2019; 5: e000524.

  • 23.

    Gholami H, Jeddi S, Zadeh-Vakili A, Farrokhfall K, Rouhollah F, Zarkesh M, et al. Transient congenital hypothyroidism alters gene expression of glucose transporters and impairs glucose sensing apparatus in young and aged offspring rats. Cell Physiol Biochem 2017; 43: 2338-2352.

  • 24.

    Mohammadi M, Zare Z. Effects of treadmill exercise on cognitive functions and anxiety-related behaviors in ovariectomized diabetic rats. Physiol Behav 2020; 224: 113021.

  • 25.

    Zare Z, Tehrani M, Zarbakhsh S, Farzadmanesh H, Shafia S, Abedinzade M, et al. Effects of paraoxon exposure on expression of apoptosis-related genes, neuronal survival, and astrocyte activation in rat prefrontal cortex. Neurotox Res 2020; 37: 356-365.

  • 26.

    Zare Z, Tehrani M, Rafiei A, Valadan R, Mohammadi M. Differential expression of glutamate transporters in cerebral cortex of paraoxon-treated rats. Neurotoxicol Teratol 2017; 62: 20-26.

  • 27.

    Andersen SL, Andersen S. Antithyroid drugs and birth defects. Thyroid Res 2020; 13: 11.

  • 28.

    Ghanbari M, Ghasemi A. Maternal hypothyroidism: An overview of current experimental models. Life Sci 2017; 187: 1-8.

  • 29.

    O'Shaughnessy KL, Wood CR, Ford RL, Kosian PA, Hotchkiss MG, Degitz SJ, Gilbert ME. Thyroid hormone disruption in the fetal and neonatal rat: predictive hormone measures and bioindicators of hormone action in the developing cortex. Toxicol Sci 2018; 166: 163-179.

  • 30.

    Dogan HO, Alcigir ME. The Protective effect of P7C3 against DNA and neuron damage in rat pups with congenital hypothyroidism. Biomed Pharmacother 2018; 99: 499-503.

  • 31.

    Alcigir ME, Dogan HO, Atalay Vural S, Yilmaz FM. Neuroprotective activity of cannabinoid receptor-2 against oxidative stress and apoptosis in rat pups having experimentally-induced congenital hypothyroidism. Dev Neurobiol 2017; 77: 1334-1347.

  • 32.

    Cattani D, Goulart PB, Cavalli VL, Winkelmann-Duarte E, Dos Santos AQ, Pierozan P, et al. Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats. Mol Cell Endocrinol 2013; 375: 14-26.

  • 33.

    Shin MS, Ko IG, Kim SE, Kim BK, Kim TS, Lee SH, et al. Treadmill exercise ameliorates symptoms of methimazole-induced hypothyroidism through enhancing neurogenesis and suppressing apoptosis in the hippocampus of rat pups. Int J Dev Neurosci 2013; 31: 214-223.

  • 34.

    Singh R, Upadhyay G, Kumar S, Kapoor A, Kumar A, Tiwari M, Godbole MM. Hypothyroidism alters the expression of Bcl-2 family genes to induce enhanced apoptosis in the developing cerebellum. J Endocrinol 2003; 176: 39-46.

  • 35.

    Mishra J, Vishwakarma J, Malik R, Gupta K, Pandey R, Maurya SK, et al. Hypothyroidism induces interleukin-1-dependent autophagy mechanism as a key mediator of hippocampal neuronal apoptosis and cognitive decline in postnatal rats. Mol Neurobiol 2021; 58: 1196-1211.

  • 36.

    Lovatel GA, Elsner VR, Bertoldi K, Vanzella C, Moyss Fdos S, Vizuete A, et al. Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus. Neurobiol Learn Mem 2013; 101: 94-102.

  • 37.

    Lu Y, Dong Y, Tucker D, Wang R, Ahmed ME, Brann D, Zhang Q. Treadmill exercise exerts neuroprotection and regulates microglial polarization and osxidative stress in a streptozotocin-induced rat model of sporadic Alzheimer's disease. J Alzheimers Dis 2017; 56: 1469-1484.

  • 38.

    Mahalakshmi B, Maurya N, Lee SD, Bharath Kumar V. Possible neuroprotective mechanisms of physical exercise in neurodegeneration. Int J Mol Sci 2020; 21.

  • 39.

    Rezaee Z, Marandi SM, Alaei H, Esfarjani F. Neuroprotective effects of endurance training in 6-hydroxydopamine rat model of Parkinson's disease. Koomesh 2020; 22: 556-562. (Persian)##https://doi.org/10.29252/koomesh.22.3.556.

  • 40.

    Zare Z, Zarbakhsh S, Tehrani M, Mohammadi M. Neuroprotective effects of treadmill exercise in hippocampus of ovariectomized and diabetic Rats. Neuroscience 2022; 496: 64-72.

  • 41.

    Guo Y, Xiao P, Lei S, Deng F, Xiao GG, Liu Y, et al. How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin (Shanghai) 2008; 40: 426-436.

  • 42.

    Wassner AJ. Congenital Hypothyroidism. Clin Perinatol 2018; 45: 1-18.