Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97201, USA.
Neuropharmacology. 2011 Sep;61(4):724-9. doi: 10.1016/j.neuropharm.2011.05.017. Epub 2011 May 27.
Allopregnanolone (ALLO) is a neurosteroid that has many functions in the brain, most notably neuroprotection and modulation of gamma-amino butyric acid (GABA) neurotransmission. Using a mouse model of cardiac arrest and cardiopulmonary resuscitation, we have previously demonstrated that ALLO protects cerebellar Purkinje cells (PCs) from ischemia in a GABA(A) receptor-dependent manner. In this study we examined the effect of sex on ALLO neuroprotection, observing that low dose ALLO (2 mg/kg) provided greater neuroprotection in females compared to males. At a higher dose of ALLO (8 mg/kg), both sexes were significantly protected from ischemic damage. Using an acute cerebellar slice preparation, whole cell voltage clamp recordings were made from PCs. Spontaneous inhibitory post synaptic currents (IPSCs) were analyzed and the response to physiological ALLO (10 nM) was significantly greater in female PCs compared to male. In contrast, recordings of miniature IPSCs, did not exhibit a sex difference in response to ALLO, suggesting that ALLO affects males and females differentially through a mechanism other than binding postsynaptic GABA(A) receptors. We conclude that the female brain has greater sensitivity to ALLO mediated potentiation of GABAergic neurotransmission, contributing to increased neuroprotection.
别孕烯醇酮（ALLO）是一种神经甾体，在大脑中有许多功能，最显著的是神经保护和调节γ-氨基丁酸（GABA）神经传递。使用心脏骤停和心肺复苏的小鼠模型，我们之前已经证明，ALLO 以 GABA(A)受体依赖的方式保护小脑浦肯野细胞（PC）免受缺血。在这项研究中，我们研究了性别对 ALLO 神经保护的影响，观察到低剂量 ALLO（2mg/kg）对雌性提供的神经保护作用大于雄性。在更高剂量的 ALLO（8mg/kg）下，两性均受到显著的缺血损伤保护。使用急性小脑切片制备，从 PCs 进行全细胞膜片钳记录。分析自发抑制性突触后电流（IPSCs），并发现生理浓度 ALLO（10nM）对雌性 PCs 的反应明显大于雄性。相比之下，对 ALLO 的反应在微小 IPSC 记录中没有表现出性别差异，这表明 ALLO 通过不同于结合突触后 GABA(A)受体的机制对男性和女性产生不同的影响。我们得出结论，女性大脑对 ALLO 介导的 GABA 能神经传递的增强作用更敏感，从而增加神经保护。
