Progesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature rats
Progesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature rats
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DOI：
10.1016/j.expneurol.2011.10.004
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发表时间：
2012-01-01
影响因子：
5.3
通讯作者：
Ikeda, Tomoaki
中科院分区：
文献类型：
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作者：
Tsuji, Masahiro;Taguchi, Akihiko;Ikeda, Tomoaki
孕酮及其代谢物异孕酮是一种神经类固醇，在胎儿大脑中浓度很高，在出生后立即减少。异孕酮是γ -氨基丁酸a （GABA(a)）受体功能的有效正调节剂。我们研究了这些类固醇外源性给药对未成熟大鼠缺氧缺血性脑病的影响。在大鼠出生后第7天（P7）、第14天（P14）和第21天（P21），在缺氧缺血后6小时和24小时立即腹腔注射黄体酮（10 mg/kg）、异孕酮（10 mg/kg）或对照物。使用组织学分析（半球体积和神经病理损伤的半定量评分）评估治疗的效果。孕酮和异孕酮均显著加重P7和P14大鼠的脑损伤，但对P21大鼠无显著影响。这种有害影响在被检查的大脑区域（皮层、纹状体、海马体和丘脑）中都是相似的，而且没有性别差异。GABA(A)受体拮抗剂双库兰的联合用药，部分减轻了异孕酮的加重作用。基于这些神经类固醇作用的相似性，我们推测黄体酮主要通过异孕酮的活性加重神经元损伤。目前的研究表明，异孕酮的有害影响，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概念是一致的。(C) 2011爱思唯尔公司版权所有。
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 gamma-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 (10 mg/kg), allopregnanolone (10 mg/kg), or vehicle alone was intraperitoneally administered immediately before and then subcutaneously 6 h and 24 h 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. (C) 2011 Elsevier Inc. All rights reserved.