Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons
Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons
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DOI：
10.1046/j.1471-4159.2001.00345.x
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发表时间：
2001-06-01
影响因子：
4.7
通讯作者：
LeBlanc, A
中科院分区：
文献类型：
--
作者：
Hammond, J;Le, Q;LeBlanc, A
雌激素是一种活性神经保护剂，目前被研究为女性阿尔茨海默病的潜在治疗方法。为了确定男性激素是否也具有神经保护作用，我们研究了生理浓度的睾酮、甲基睾酮和表雄酮对原代培养的人神经元在血清剥夺诱导下发生凋亡的影响。血清剥夺显著诱导神经细胞的长期凋亡。正如预期的那样，生理浓度的17-β-雌二醇和转录不活跃的17-α-雌二醇可以保护神经元免受凋亡的影响。与17-β-雌二醇类似，生理浓度的睾酮也具有神经保护作用。在神经元培养中，雄激素受体以8+/-2fmol/mg蛋白存在。非芳香化雄激素米博利酮也具有神经保护作用，而芳香酶抑制剂4-雄酮-4-醇-3，17-二酮不能阻止睾酮介导的神经保护作用。相比之下，抗雄激素药氟他胺消除了睾酮介导的神经保护。睾酮类似物甲基睾酮显示了雄激素受体依赖性的神经保护作用，这种保护作用随着时间的推移而延迟，表明代谢物可能是活性物质。内源性抗雄激素表雄酮也显示出轻微的神经保护作用，但不是通过雄激素受体。这些结果表明，雄激素通过雄激素受体直接诱导神经保护。这些数据表明，雄激素也可能对老年男性的阿尔茨海默氏症有治疗价值。
Estrogen is an active neuroprotectant and is presently investigated as a potential therapy against Alzheimer's disease for women. To determine if male hormones could also be neuroprotective, we investigated the effect of testosterone, methyltestosterone, and epitestosterone at physiological concentrations on primary cultures of human neurons induced to undergo apoptosis by serum deprivation. Serum deprivation significantly induces neuronal apoptosis in a protracted fashion. As expected, physiological concentrations of 17-beta -estradiol and transcriptionally inactive 17-alpha -estradiol protect neurons against apoptosis. Similar to 17-beta -estradiol, physiological concentrations of testosterone are also neuroprotective. Androgen receptors are present at 8 +/- 2 fmol/mg protein in the neuron cultures. The non-aromatizable androgen, mibolerone, is also neuroprotective and aromatase inhibitor, 4-androsten-4-OL-3,17-dione, does not prevent testosterone-mediated neuroprotection. In contrast, anti-androgen, flutamide, eliminates testosterone-mediated neuroprotection. Testosterone analog, methyltestosterone, showed androgen receptor-dependent neuroprotection that was delayed in time indicating that a metabolite may be the active agent. The endogenous anti-androgen, epitestosterone, also showed a slight neuroprotective effect but not through the androgen receptor. These results indicate that androgens induce neuroprotection directly through the androgen receptor. These data suggest that androgens may also be of therapeutic value against Alzheimer's disease in aging males.