Expression of HIF-1α, TFRC-1 and TIM-2 Relative mRNA Levels in PTZ-Kindling Model of Epilepsy

Year 2020, Volume: 12 Issue: 2, 947 - 954, 05.01.2020

Hüseyin Emre Dündar Aslıhan Öztaş Saliha Rabia Şahin Seher Yilmaz Furkan Kocabaş Enes Akyüz

https://doi.org/10.37212/jcnos.829166

Abstract

Epilepsy is a neurological disease characterized by abnormal electrical activity and recurrent seizures in the central nervous system (CNS). Changes in hypoxia and iron metabolism can stimulate seizures through the CNS and cardiac system. Cardiovascular system disorders such as arrhythmias also accompany this process. It was aimed to examine the genes of TFRC-1 and TIM-2, which contribute to ion homeostasis by providing hypoxia inducible factor (HIF) -1 and intracellular iron flow, through the kindled model of pentylenetetrazol (PTZ). HIF-1α, TFRC-1 and TIM-2 gene expressions were investigated in both brain and heart tissue by RT-PCR method. As a result of the data, TIM-2 expression significantly decreased in the brain (p<0.01) and cardiac ventricle tissue (p<0.05) in female rats. TFRC-1 gene expression decreased in female brain tissue (p<0.05). Our findings suggest that TFRC-1 and TIM-2 gene modulation may have therapeutic potential in epilepsy patients. In addition, TFRC-1 and TIM-2 genes may contribute to ferroptosis and oxidative stress mechanisms known to be associated with the seizure process by regulating iron transfer into the cell. It is crucial to conduct new studies on behalf of the future to elucidate iron metabolism in epilepsy through the TIM-2 and TFRC-1 genes.

Keywords

Epilepsy, PTZ-kindling model, HIF-1α, TFRC-1, TIM-2

Supporting Institution

The Scientific and Technological Research Council of Turkey (TUBITAK)

Project Number

1919B011902615

References

• Auzmendi J, Buchholz B, Salguero J, Cañellas C, Kelly J, Men P, Zubillaga M, Rossi A, Merelli A, Gelpi RJ, Ramos AJ, Lazarowski A. (2018). Pilocarpine-Induced Status Epilepticus Is Associated with P-Glycoprotein Induction in Cardiomyocytes, Electrocardiographic Changes, and Sudden Death. Pharmaceuticals (Basel) 11.
• Biet M, Morin N, Lessard-Beaudoin M, Graham RK, Duss S, Gagné J, Sanon NT, Carmant L, Dumaine R. (2015). Prolongation of action potential duration and QT interval during epilepsy linked to increased contribution of neuronal sodium channels to cardiac late Na+ current: potential mechanism for sudden death in epilepsy. Circ Arrhythm Electrophysiol. 8:912-920.
• Brewster AL, Marzec K, Hairston A, Ho M, Anderson AE, Lai YC. (2016). Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy. Epilepsia. 57:1907-1915.
• Brodie MJ, Zuberi SM, Scheffer IE, Fisher RS. (2018). The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? Epileptic Disord. 20:77-87.
• Cozzi A, Rovelli E, Frizzale G, Campanella A, Amendola M, Arosio P, Levi S. (2010). Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy. Neurobiol Dis. 37:77-85.
• Darby IA, Hewitson TD. (2016). Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 365:553-562.
• Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, Rajbhandari P, Stokes ME, Bender HG, Csuka JM, Upadhyayula PS, Canoll P, Uchida K, Soni RK, Hadian K, Stockwell BR. (2020). Transferrin Receptor Is a Specific Ferroptosis Marker. Cell Rep. 30(10):3411-23. e7.
• Gorter JA, Mesquita AR, van Vliet EA, da Silva FH, Aronica E. (2005). Increased expression of ferritin, an iron-storage protein, in specific regions of the parahippocampal cortex of epileptic rats. Epilepsia. 46:1371-1379.
• Jiang G, Zhou R, He X, Shi Z, Huang M, Yu J, Wang X. (2016). Expression levels of microRNA-199 and hypoxia-inducible factor-1 alpha in brain tissue of patients with intractable epilepsy. Int J Neurosci. 126:326-334.
• Kadima NT, Kobau R, Zack MM, Helmers S. (2013). Comorbidity in adults with epilepsy--United States, 2010. MMWR Morb Mortal Wkly Rep. 62:849-853.
• Keezer MR, Sisodiya SM, Sander JW. (2016). Comorbidities of epilepsy: current concepts and future perspectives. Lancet Neurol. 15:106-115.
• Lai YC, Li N, Lawrence W, Wang S, Levine A, Burchhardt DM, Pautler RG, Valderrábano M, Wehrens XH, Anderson AE. (2018). Myocardial remodeling and susceptibility to ventricular tachycardia in a model of chronic epilepsy. Epilepsia open 3:213-223.
• Lakaye B, de Borman B, Minet A, Arckens L, Vergnes M, Marescaux C, Grisar T. (2000). Increased expression of mRNA encoding ferritin heavy chain in brain structures of a rat model of absence epilepsy. Exp Neurol. 162:112-120.
• Li J, Jiang G, Chen Y, Chen L, Li Z, Wang Z, Wang X. (2014). Altered expression of hypoxia-Inducible factor-1α participates in the epileptogenesis in animal models. Synapse. 68:402-409.
• Ma Y. (2018). The Challenge of microRNA as a Biomarker of Epilepsy. Curr Neuropharmacol. 16:37-42.
• Mao XY, Zhou HH, Jin WL. (2019). Ferroptosis Induction in Pentylenetetrazole Kindling and Pilocarpine-Induced Epileptic Seizures in Mice. Front Neurosci. 13:721.
• Marino B, Digilio MC. (2000). Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol. 9:303-315.
• McQuillen PS, Miller SP. (2010). Congenital heart disease and brain development. Ann N Y Acad Sci. 1184:68-86.
• Merelli A, Rodríguez JCG, Folch J, Regueiro MR, Camins A, Lazarowski A. (2018). Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities. Curr Neuropharmacol. 16:1484-1498.
• Miller G, Vogel H. (1999). Structural evidence of injury or malformation in the brains of children with congenital heart disease. Semin Pediatr Neurol. p 20-26.
• Nakamura T, Naguro I, Ichijo H. (2019). Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochim Biophys Acta Gen Subj. 1863:1398-1409.
• Neligan A, Bell GS, Johnson AL, Goodridge DM, Shorvon SD, Sander JW. (2011). The long-term risk of premature mortality in people with epilepsy. Brain. 134:388-395.
• Neligan A, Hauser WA, Sander JW. (2012). The epidemiology of the epilepsies. Handb Clin Neurol. 107:113-33.
• Schultz K, Fanburg BL, Beasley D. (2006). Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol. 290:H2528-2534.
• Shimoda LA, Semenza GL. (2011). HIF and the lung: role of hypoxia-inducible factors in pulmonary development and disease. Am J Respir Crit Care Med. 183:152-156.
• Simon RP. (2016). Epigenetic modulation of gene expression governs the brain's response to injury. Neurosci Lett. 625:16-19.
• Steinlein OK. (2004). Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci. 5:400-408.
• Thijs RD, Surges R, O'Brien TJ, Sander JW. (2019). Epilepsy in adults. Lancet. 393:689-701.
• Todorich B, Zhang X, Slagle-Webb B, Seaman WE, Connor JR. (2008). Tim-2 is the receptor for H-ferritin on oligodendrocytes. J Neurochem. 107:1495-1505.
• Xu W, Barrientos T, Mao L, Rockman HA, Sauve AA, Andrews NC. (2015). Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep. 13:533-545.
• Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. (1998). Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol. 275:L818-826.