Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishiro-dai, Suita, Osaka, 565-8565, Japan.
Exp Neurol. 2012 Jan;233(1):214-20. doi: 10.1016/j.expneurol.2011.10.004. Epub 2011 Oct 14.
Progesterone and its metabolite, allopregnanolone, are neurosteroids that are present at high concentrations in fetal brains that decrease right after birth. Allopregnanolone is a potent positive modulator of γ-aminobutyric acid A (GABA(A)) receptor function. We examined the effect of exogenous administration of these steroids on hypoxic-ischemic encephalopathy in immature rats. Progesterone (10mg/kg), allopregnanolone (10mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6h and 24h after hypoxia-ischemia to postnatal day 7 (P7), day 14 (P14), and day 21 (P21) rats. The effects of the treatments were evaluated using histological analyses (hemispheric volumes and semi-quantitative scoring for neuropathologic injury). Both progesterone and allopregnanolone significantly exacerbated brain injury in P7 and P14 rats, but not in P21 rats. This detrimental effect was similar across the examined brain regions (the cortex, striatum, hippocampus, and thalamus) and showed no sex differences. Co-administration of the GABA(A) receptor antagonist, bicuculline, partially mitigated the exacerbating effect of allopregnanolone. Based on the similarity of the effects of these neurosteroids, we speculate that progesterone accentuates neuronal injury mainly via the activity of allopregnanolone. The present study indicates that the detrimental effects of allopregnanolone were, at least in part, mediated via GABAergic neuroexcitability. This is in line with the notion that GABA is excitatory for immature neurons, while it is inhibitory for mature neurons.
孕酮及其代谢产物孕烷醇酮是神经甾体，在胎脑中浓度很高，出生后立即下降。孕烷醇酮是γ-氨基丁酸 A（GABA(A)）受体功能的有效正调节剂。我们研究了外源性给予这些类固醇对未成熟大鼠缺氧缺血性脑病的影响。孕酮（10mg/kg）、孕烷醇酮（10mg/kg）或单独载体在缺氧缺血前立即腹膜内给药，然后在缺氧缺血后 6 小时和 24 小时皮下给药至出生后第 7 天（P7）、第 14 天（P14）和第 21 天（P21）大鼠。通过组织学分析（半球体积和神经病理学损伤的半定量评分）评估治疗效果。孕酮和孕烷醇酮均显著加重了 P7 和 P14 大鼠的脑损伤，但对 P21 大鼠没有影响。这种有害作用在检查的脑区（皮质、纹状体、海马和丘脑）之间是相似的，并且没有性别差异。GABA(A)受体拮抗剂bicuculline 的共同给药部分减轻了孕烷醇酮的加重作用。基于这些神经甾体的作用相似，我们推测孕酮主要通过孕烷醇酮的活性加重神经元损伤。本研究表明，孕烷醇酮的有害作用至少部分是通过 GABA 能神经兴奋性介导的。这与 GABA 对未成熟神经元具有兴奋性，而对成熟神经元具有抑制性的观点一致。
