Neurosteroids and epileptogenesis in the pilocarpine model: Evidence for a relationship between P450scc induction and length of the latent period
Neurosteroids and epileptogenesis in the pilocarpine model: Evidence for a relationship between P450scc induction and length of the latent period
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DOI：
10.1111/j.1528-1167.2008.01971.x
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发表时间：
2009-01-01
期刊：
影响因子：
5.6
通讯作者：
Avoli, Massimo
中科院分区：
文献类型：
--
作者：
Biagini, Giuseppe;Longo, Daniela;Avoli, Massimo
细胞色素P450胆固醇侧链裂解酶（P450 SCC）催化脑内神经类固醇生物合成的初始步骤。我们试图确定哪些细胞表达P450 cc，以及神经类固醇是否在匹罗卡品诱导的癫痫持续状态（SE）后的癫痫发生中起调节作用。大鼠在60、120、140、150用抗P450 SCC血清和抗GFAP单克隆抗体双重免疫标记法检测海马CA 3区P450 SCC的诱导SE与海马CA 3放射层和陷窝-分子层中许多星形胶质细胞和少量小胶质细胞和少突胶质细胞中的P450 SCC诱导相关。P450 SCC的诱导程度随着SE持续时间的增加而增加。奇怪的是，增加P450 SCC诱导大鼠经历SE为180分钟或更长时间与自发复发性癫痫发作的延迟。用5 α-还原酶抑制剂非那肽治疗（100 mg/kg/天，持续25天），其抑制γ-氨基丁酸（GABA）（A）受体调节神经类固醇如别孕烯醇酮的合成，与暴露于180分钟而非90分钟的大鼠自发性癫痫发作时间显著减少相关。在海马神经胶质细胞的不同群体中，SE诱导P450 SCC。P450 SCC的诱导与自发性癫痫发作的延迟有关。相反，抑制神经类固醇的合成加速自发性癫痫发作，但只有在动物表现出显着增加P450 SCC。这些发现表明，诱导神经类固醇合成反应性胶质细胞与延迟发作的自发性复发性癫痫发作。
Cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) catalyzes the initial step in the biosynthesis of neurosteroids within the brain. We sought to determine which cells express P450cc and whether neurosteroids play a role in the regulation of epileptogenesis following pilocarpine-induced status epilepticus (SE).Rats experienced uninterrupted SE or SE terminated with diazepam at 60, 120, and 180 min. P450scc induction in CA3 hippocampus was determined by double immunolabeling with P450scc antiserum and monoclonal antibodies against GFAP (astrocytes), RIP (oligodendrocytes), or heme oxygenase-1 (microglia).SE was associated with P450scc induction in many astrocytes and a small number of microglia and oligodendrocytes in the hippocampal CA3 strata radiatum and lacunosum-moleculare. The extent of P450scc induction increased with increasing SE duration. Paradoxically, increased P450scc induction in rats experiencing SE for 180 min or more was associated with the delayed onset of spontaneous recurrent seizures. Treatment with the 5 alpha-reductase inhibitor finasteride (100 mg/kg/day for 25 days), which inhibits the synthesis of gamma-aminobutyric acid (GABA)(A) receptor modulating neurosteroids such as allopregnanolone, was associated with a significant reduction in time to the onset of spontaneous seizures in rats exposed to 180-min but not 90-min SE.P450scc is induced by SE in a diverse population of hippocampal glia. Induction of P450scc is associated with the delayed onset of spontaneous seizures. Conversely, inhibition of neurosteroid synthesis accelerated the onset of spontaneous seizures, but only in animals exhibiting significant increases in P450scc. These findings suggest that induction of neurosteroid synthesis in reactive glial cells is associated with delayed onset of spontaneously recurrent seizures.