Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima 739-8521, Japan.
J Steroid Biochem Mol Biol. 2013 May;135:1-6. doi: 10.1016/j.jsbmb.2012.12.013. Epub 2012 Dec 29.
Increasing evidence shows that progesterone, a neuroactive steroid, has protective actions in central nervous system, but there is little evidence to show the protective mechanism of progesterone on neurotoxicity induced by environmental chemicals. In this study, we examined the effects of progesterone on neuronal injury induced by tributyltin (TBT) in rat hippocampal slices. Treatment with progesterone dose-dependently suppressed hippocampal neuronal injury induced by TBT. The neuroprotective action of progesterone was completely canceled with pretreatment by finasteride, a 5α-reductase inhibitor, but it was not affected by mifepristone, a progesterone receptor antagonist, or by SU-10603, a cytochrome P450 17α inhibitor. The content of allopregnanolone in the slices was significantly increased by treatment with progesterone, and this increment was greatly suppressed with a pretreatment of finasteride. Treatment with allopregnanolone attenuated neuronal injury induced by TBT in a dose-dependent manner. The neuroprotective effects not only of progesterone but also of allopregnanolone were canceled by bicuculline, a potent gamma-aminobutyric acid A (GABAA) receptor antagonist. Pretreatment with muscimol, a GABAA receptor agonist, attenuated hippocampal neuronal injury elicited by TBT. Taken together, allopregnanolone converted from progesterone in hippocampal slices could protect neurons from TBT-induced neurotoxicity due to a GABAA receptor-dependent mechanism. One of the physiological roles of neuroactive steroids might be neuroprotection from environmental chemicals.
越来越多的证据表明，神经活性甾体孕激素在中枢神经系统中具有保护作用，但几乎没有证据表明孕激素对环境化学物质引起的神经毒性具有保护机制。在这项研究中，我们研究了孕激素对大鼠海马切片中海豚烯醇酮诱导的神经元损伤的影响。孕激素处理呈剂量依赖性地抑制 TBT 诱导的海马神经元损伤。5α-还原酶抑制剂非那雄胺预处理完全消除了孕激素的神经保护作用，但孕激素受体拮抗剂米非司酮或细胞色素 P45017α 抑制剂 SU-10603 对其没有影响。孕激素处理显著增加了切片中异孕烯醇酮的含量，而非那雄胺预处理大大抑制了这种增加。异孕烯醇酮呈剂量依赖性地减弱 TBT 诱导的神经元损伤。孕激素和异孕烯醇酮的神经保护作用均被 GABA A 受体拮抗剂荷包牡丹碱所阻断。GABA A 受体激动剂 muscimol 的预处理减弱了 TBT 引起的海马神经元损伤。综上所述，海马切片中由孕激素转化而来的异孕烯醇酮可能通过 GABA A 受体依赖性机制保护神经元免受 TBT 诱导的神经毒性。神经活性甾体的生理作用之一可能是保护神经元免受环境化学物质的侵害。
