Progesterone increases brain-derived neurotrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants
Progesterone increases brain-derived neurotrophic factor expression and protects against glutamate toxicity in a mitogen-activated protein kinase- and phosphoinositide-3 kinase-dependent manner in cerebral cortical explants
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DOI：
10.1002/jnr.21370
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发表时间：
2007-08-15
影响因子：
4.2
通讯作者：
Singh, Meharvan
中科院分区：
文献类型：
--
作者：
Kaur, Paramjit;Jodhka, Parmeet K.;Singh, Meharvan
女性阿尔茨海默病的患病率和风险高于男性，部分原因是更年期后女性性腺激素水平急剧下降。尽管人们对雌激素丢失的后果以及雌激素的神经保护潜力给予了相当大的关注，但重要的是要认识到，更年期也会导致孕酮水平的急剧下降。事实上，黄体酮具有神经保护作用，尽管涉及的确切机制尚不清楚。根据我们先前观察到的孕酮引起ERK和Akt的磷酸化，这两个通路分别是神经保护性丝裂原活化蛋白激酶(MAPK)和磷酸肌醇3激酶(P13-K)通路的关键效应者，我们确定了这两个通路中的任何一个的激活是否是孕酮诱导的保护所必需的。通过大脑皮层器官型外植体(切片培养)，我们发现孕酮对谷氨酸诱导的毒性具有保护作用。此外，这些保护作用被MEK1/2抑制剂UO126或P13-K抑制剂LY294002所抑制，这支持了孕酮诱导的保护中MAPK和P13-K通路的要求。此外，在与我们的神经保护数据一致的治疗浓度和持续时间下，黄体酮还在蛋白质和mRNA水平上增加了脑源性神经营养因子(BDNF)的表达。BDNF的这种诱导可能与孕酮的保护作用有关，K252a通过抑制Trk信号抑制孕酮的保护作用。总而言之，这些数据表明，黄体酮通过多种可能相关的机制起到保护作用。(C)2007年Wiley-Liss，Inc.
The higher prevalence and risk for Alzheimer's disease in women relative to men has been partially attributed to the precipitous decline in gonadal hormone levels that occurs in women following the menopause. Although considerable attention has been focused on the consequence of estrogen loss, and thus estrogen's neuroprotective potential, it is important to recognize that the menopause results in a precipitous decline in progesterone levels as well. In fact, progesterone is neuroprotective, although the precise mechanisms involved remain unclear. Based on our previous observation that progesterone elicits the phosphorylation of ERK and Akt, key effectors of the neuroprotective mitogen-activated protein kinase (MAPK) and phosphoinositicle-3 kinase (P13-K) pathways, respectively, we determined whether activation of either of these pathways was necessary for progesterone-induced protection. With organotypic explants (slice culture) of the cerebral cortex, we found that progesterone protected against glutamate-induced toxicity. Furthermore, these protective effects were inhibited by either the MEK1/2 inhibitor UO126 or the P13-K inhibitor LY294002, supporting the requirement for both the MAPK and P13-K pathways in progesterone-induced protection. In addition, at a concentration and duration of treatment consistent with our neuroprotection data, progesterone also increased the expression of brain-derived neurotrophic factor (BDNF), at the level of both protein and mRNA. This induction of BDNF may be relevant to the protective effects of progesterone, in that inhibition of Trk signaling, with K252a, inhibited the protective effects of progesterone. Collectively, these data suggest that progesterone is protective via multiple and potentially related mechanisms. (C) 2007 Wiley-Liss, Inc.