Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
Steroids. 2011 Aug;76(9):845-55. doi: 10.1016/j.steroids.2011.02.013. Epub 2011 Mar 1.
The therapeutic use of progesterone following traumatic brain injury has recently entered phase III clinical trials as a means of neuroprotection. Although it has been hypothesized that progesterone protects against calcium overload following excitotoxic shock, the exact mechanisms underlying the beneficial effects of progesterone have yet to be determined. We found that therapeutic concentrations of progesterone to be neuroprotective against depolarization-induced excitotoxicity in cultured striatal neurons. Through use of calcium imaging, electrophysiology and the measurement of changes in activity-dependent gene expression, progesterone was found to block calcium entry through voltage-gated calcium channels, leading to alterations in the signaling of the activity-dependent transcription factors NFAT and CREB. The effects of progesterone were highly specific to this steroid hormone, although they did not appear to be receptor mediated. In addition, progesterone did not inhibit AMPA or NMDA receptor signaling. This analysis regarding the effect of progesterone on calcium signaling provides both a putative mechanism by which progesterone acts as a neuroprotectant, as well as affords a greater appreciation for its potential far-reaching effects on cellular function.
孕激素在创伤性脑损伤后的治疗用途最近已经进入 III 期临床试验，作为神经保护的一种手段。虽然有人假设孕激素可以防止兴奋毒性休克后钙超载，但孕激素发挥有益作用的确切机制仍有待确定。我们发现治疗浓度的孕激素可防止培养的纹状体神经元去极化诱导的兴奋性毒性。通过钙成像、电生理学和活性依赖性基因表达变化的测量，发现孕激素通过电压门控钙通道阻断钙内流，导致活性依赖性转录因子 NFAT 和 CREB 的信号转导发生改变。孕激素的作用对这种甾体激素具有高度特异性，尽管它们似乎不是受体介导的。此外，孕激素不抑制 AMPA 或 NMDA 受体信号。关于孕激素对钙信号的影响的这种分析不仅提供了孕激素作为神经保护剂的作用机制，而且使人们更加了解其对细胞功能的潜在深远影响。
