Boussadia B, Ghosh C, Plaud C, Pascussi J M, de Bock F, Rousset M C, Janigro D, Marchi N
Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Centre National Recherche Scientifique (CNRS), Montpellier, France.
Cerebrovascular Research Center, Department of Biomedical Engineering and Molecular Medicine, Cleveland Clinic, USA.
Neuroscience. 2014 Dec 5;281:124-34. doi: 10.1016/j.neuroscience.2014.09.055. Epub 2014 Oct 2.
P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18-24h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain.
细胞色素P450代谢酶在人和啮齿动物的大脑中均有表达。近期数据支持它们参与癫痫的病理生理学过程。然而，癫痫大脑中代谢酶表达的决定因素尚不清楚。我们检验了以下假设：癫痫持续状态（SE）或接触苯妥英或苯巴比妥会影响代谢酶CYP2E1在大脑中的表达。通过全身注射海藻酸在C57BL/6J小鼠中诱导癫痫持续状态。在严重癫痫持续状态发作18 - 24小时后，通过免疫组织化学评估大脑CYP2E1的表达。通过共聚焦显微镜确定其与神经元细胞核（NEUN）、胶质纤维酸性蛋白（GFAP）和CD31的共定位。在体内或使用体外海马脑片培养评估苯妥英、卡马西平和苯巴比妥对CYP2E1表达的影响。在一组耐药性癫痫患者的脑切除标本和人内皮细胞培养物（EPI - EC）中研究CYP2E1的表达。免疫组织化学显示，在小鼠严重癫痫持续状态发作后，CYP2E1表达增加，且仅限于海马CA2/3区和门区神经元。在。在星形胶质细胞 - 血管界面也观察到CYP2E1表达。对人脑标本的分析显示，CYP2E1在神经元和血管内皮细胞（EC）中表达。CYP2E1在培养的人内皮细胞中表达，并在EPI - EC中过表达。在分析药物暴露对CYP2E1表达的影响时，我们发现，无论在体内还是体外，乙醇都会增加大脑和肝脏中CYP2E1的水平。苯妥英治疗可诱导大脑中局部CYP2E1表达，而卡马西平和苯巴比妥则无显著影响。我们的数据表明，急性癫痫持续状态对大脑CYP2E1表达的影响具有局限性且具有细胞特异性。接触特定的抗癫痫药物可能在决定CYP2E在大脑中的表达方面发挥作用。需要进一步研究以全面重现人类癫痫大脑中观察到的细胞色素P450酶表达的相关因素。
