DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats
DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats
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DHEA-大鼠短暂性脑缺血后的神经保护和神经毒性
DOI：
10.1038/jcbfm.2008.118
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发表时间：
2009-02-01
影响因子：
6.3
通讯作者：
Chen, Ling
中科院分区：
文献类型：
--
作者：
Li, Zhen;Cui, Shengzhong;Chen, Ling
脱氢表雄酮(DHEA)不仅可以预防N-甲基-D-天冬氨酸(NMDAR)引起的神经毒性，而且可以通过NMDAR促进钙离子内流。然而，这些脱氢表雄酮效应会导致神经元损伤的结果不一致，在缺血诱导的脑损伤中还没有得到很好的研究。在此，我们报道了在大鼠短暂性全脑缺血后3~48h内单次给予DHEA(20 mg/kg)具有神经保护作用，如减少缺血诱导的海马神经元死亡和改善缺血诱导的空间学习障碍。相反，在缺血前或缺血后1h，给予脱氢表雄酮加重了缺血诱导的神经元死亡和学习障碍。这种DHEA神经毒性似乎是由DHEA本身引起的，但不是通过其代谢物睾酮引起的，并可被NMDAR阻滞剂MK801或sigma-1(sigma(1))受体拮抗剂NE100预先抑制。然而，DHEA的神经保护作用被NE100阻断。这些结果表明，DHEA不仅提供了强大的缺血神经保护作用，治疗机会长，而且在缺血和再灌注早期给药也具有神经毒性，这表明DHEA在临床治疗包括中风在内的短暂性脑缺血所致脑损伤中的重要性。
Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca2+ influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.