Progesterone receptor membrane component 2 regulates the neuronal activity and participates in epileptic seizures in experimental mice

Abstract

It was found the expression of progesterone receptor membrane component 2 (PGRMC2) in the histone of epileptic mice was lower than that of normal mice. In this study, we found by the immunofluorescence technique, PGRMC2 was expressed in both astrocytes and neurons of the mouse hippocampus. In addition, the seizure latency and seizure grade of mice in each group were observed after stereotactic injection of the PGRMC2 knockdown virus, PGRMC2 overexpression lentivirus, and related null virus into the hippocampus of mice. It was found that the seizure latency of mice in the PTZ + siPGRMC2 group was prolonged compared with the null virus group. The seizure latency was shortened in the PTZ + PGRMC2 group. The number of grade IV and above seizures in the PTZ + siPGRMC2 group was significantly reduced, while the number of grade IV and above seizures in the PTZ + PGRMC2 group was significantly increased. It was found that the nerve cells in the PTZ + siPGRMC2 group were still intact. In the PTZ + PGRMC2 group, the neural cells were damaged, the intercellular space was widened, and the number of cells was reduced. These findings support that PGRMC2 may be involved in epileptic seizures.

Keywords

astrocytes / epilepsy / hippocampus / neurons / progesterone receptor membrane component 2

References

[1] Fisher RS, Cross JH, D’Souza C, et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017;58(4):531-542.

[2] Guerrini R, Marini C, Barba C. Generalized epilepsies. Handb Clin Neurol. 2019;161:3-15.

[3] Scharfman HE. The neurobiology of epilepsy. Curr Neurol Neurosci Rep. 2007;7(4):348-354.

[4] Megiddo I, Colson A, Chisholm D, Dua T, Nandi A, Laxminarayan R. Health and economic benefits of public financing of epilepsy treatment in India: an agent-based simulation model. Epilepsia. 2016;57(3):464-474.

[5] Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet. 2015;385(9971):884-898.

[6] Ricart JJ. Drug-resistant epilepsy. N Engl J Med. 2011;365(23):2239.

[7] Xue-Ping W, Hai-Jiao W, Li-Na Z, Xu D, Ling L. Risk factors for drug-resistant epilepsy: a systematic review and meta-analysis. Medicine. 2019;98(30):e16402.

[8] Brodie MJ. Pharmacological treatment of drug-resistant epilepsy in adults: a practical guide. Curr Neurol Neurosci Rep. 2016;16(9):82.

[9] Naimo GD, Guarnaccia M, Sprovieri T, et al. A systems biology approach for personalized medicine in refractory epilepsy. Int J Mol Sci. 2019;20(15):3717.

[10] Hussain SA, Ortendahl JD, Bentley TGK, et al. The economic burden of caregiving in epilepsy: an estimate based on a survey of US caregivers. Epilepsia. 2020;61(2):319-329.

[11] Singh G, Sander JW. The global burden of epilepsy report: implications for low-and middle-income countries. Epilepsy Behav. 2020;105:106949.

[12] Yan R, Zhang HQ, Wang J, et al. Application value of molecular imaging technology in epilepsy. Ibrain. 2021;7(3):200-210.

[13] Akyuz E, Polat AK, Eroglu E, Kullu I, Angelopoulou E, Paudel YN. Revisiting the role of neurotransmitters in epilepsy: an updated review. Life Sci. 2021;265:118826.

[14] Wei F, Yan LM, Su T, et al. Ion channel genes and epilepsy: functional alteration, pathogenic potential, and mechanism of epilepsy. Neurosci Bull. 2017;33(4):455-477.

[15] Devinsky O, Vezzani A, Najjar S, De Lanerolle NC, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 2013;36(3):174-184.

[16] Perucca P, Bahlo M, Berkovic SF. The genetics of epilepsy. Annu Rev Genomics Hum Genet. 2020;21:205-230.

[17] Geis C, Planagumà J, Carreño M, Graus F, Dalmau J. Autoimmune seizures and epilepsy. J Clin Invest. 2019;129(3):926-940.

[18] Levite M, Goldberg H. Autoimmune epilepsy—novel multidisciplinary analysis, discoveries and insights. Front Immunol. 2022;12:762743.

[19] Li X, Yang C, Shi Y, et al. Abnormal neuronal damage and inflammation in the hippocampus of kainic acid-induced epilepsy mice. Cell Biochem Funct. 2021;39(6):791-801.

[20] Adamczyk B, Węgrzyn K, Wilczyński T, Maciarz J, Morawiec N, Adamczyk-Sowa M. The most common lesions detected by neuroimaging as causes of epilepsy. Medicina. 2021;57(3):294.

[21] Pitkanen A. Drug-mediated neuroprotection and antiepileptogenesis: animal data. Neurology. 2002;59(9 suppl 5): S27-S33.

[22] Duncan JS. Seizure-induced neuronal injury: human data. Neurology. 2002;59(9 suppl 5): S15-S20.

[23] Intlekofer KA, Petersen SL. Distribution of mRNAs encoding classical progestin receptor, progesterone membrane components 1 and 2, serpine mRNA binding protein 1, and progestin and ADIPOQ receptor family members 7 and 8 in rat forebrain. Neuroscience. 2011;172:55-65.

[24] Petersen SL, Intlekofer KA, Moura-Conlon PJ, Brewer DN, Del Pino Sans J, Lopez JA. Novel progesterone receptors: neural localization and possible functions. Front Neurosci. 2013;7:164.

[25] Devinsky O, Vezzani A, O’Brien TJ, et al. Epilepsy. Nat Rev Dis Primers. 2018;4:18024.

[26] Sofroniew MV. Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol. 2020;41(9):758-770.

[27] Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nature Neurosci. 2019;22(2):154-166.

[28] McKee CA, Lananna BV, Musiek ES. Circadian regulation of astrocyte function: implications for Alzheimer’s disease. Cell Mol Life Sci. 2020;77(6):1049-1058.

[29] Łukawski K, Andres-Mach M, Czuczwar M, Łuszczki JJ, Kruszyński K, Czuczwar SJ. Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies. Pharmacol Rep. 2018;70(2):284-293.

[30] Pitkänen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol. 2011;10(2):173-186.

[31] Wilcox KS, Gee JM, Gibbons MB, Tvrdik P, White JA. Altered structure and function of astrocytes following status epilepticus. Epilepsy Behav. 2015;49:17-19.

[32] Coulter DA, Steinhauser C. Role of astrocytes in epilepsy. Cold Spring Harbor Perspect Med. 2015;5(3):a022434.

[33] Guo D, Zou J, Wong M. Rapamycin attenuates acute seizure-induced astrocyte injury in mice in vivo. Sci Rep. 2017;7(1):2867.

[34] Meffre D, Delespierre B, Gouézou M, et al. The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury. J Neurochem. 2005;93(5):1314-1326.

[35] Faller M, Matsunaga M, Yin S, Loo JA, Guo F. Heme is involved in microRNA processing. Nat Struct Mol Biol. 2007;14(1):23-29.

[36] Chan F, Lax NZ, Voss CM, et al. The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction. Brain. 2019;142(2):391-411.

[37] Kumar A, Chugani HT. The role of radionuclide imaging in epilepsy, part 1: sporadic temporal and extratemporal lobe epilepsy. J Nucl Med Technol. 2013;54(10):1775-1781.

[38] Popova I, Malkov A, Ivanov AI, et al. Metabolic correction by pyruvate halts acquired epilepsy in multiple rodent models. Neurobiol Dis. 2017;106:244-254.

[39] Galmozzi A, Kok BP, Kim AS, et al. PGRMC2 is an intracellular haem chaperone critical for adipocyte function. Nature. 2019;576(7785):138-142.

[40] Habibi M, Hart F, Bainbridge J. The impact of psychoactive drugs on seizures and antiepileptic drugs. Curr Neurol Neurosci Rep. 2016;16(8):71.

[41] Boison D, Steinhäuser C. Epilepsy and astrocyte energy metabolism. GLIA. 2018;66(6):1235-1243.

[42] Heuser K, Nome CG, Pettersen KH, et al. Ca2+signals in astrocytes facilitate spread of epileptiform activity. Cereb Cortex. 2018;28(11):4036-4048.

[43] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7-35.

[44] Gómez-Gonzalo M, Martin-Fernandez M, Martínez-Murillo R, et al. Neuron-astrocyte signaling is preserved in the aging brain. GLIA. 2017;65(4):569-580.

[45] Pascual O, Casper KB, Kubera C, et al. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005;310(5745):113-116.

[46] Clasadonte J, Poulain P, Hanchate NK, Corfas G, Ojeda SR, Prevot V. Prostaglandin e2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation. Proc Natl Acad Sci. 2011;108(38):16104-16109.

[47] Striano P, Minassian BA. From genetic testing to precision medicine in epilepsy. Neurotherapeutics. 2020;17(2):609-615.

[48] Salpekar J. Neuropsychiatric effects of epilepsy in developmental disorders. Curr Opin Psychiatry. 2018;31(2):109-115.

[49] Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5(7):380-391.

[50] Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.

[51] Hattiangady B, Shetty AK. Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy. Epilepsia. 2008;49(suppl 5):26-41.

[52] Cao J, Tang C, Gao M, et al. Hyperoside alleviates epilepsy-induced neuronal damage by enhancing antioxidant levels and reducing autophagy. J Ethnopharmacol. 2020;257:112884.

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2023 The Authors. Ibrain published by Affiliated Hospital of Zunyi Medical University (AHZMU) and Wiley-VCH GmbH.