Activation of a membrane-associated androgen receptor promotes cell death in primary cortical astrocytes
Activation of a membrane-associated androgen receptor promotes cell death in primary cortical astrocytes
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DOI：
10.1210/en.2006-1443
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Singh, Meharvan
中科院分区：
文献类型：
--
作者：
Gatson, Joshua W.;Singh, Meharvan
在中枢神经系统，雄激素既可以起到保护作用，也可以起到促进损伤的作用。例如，睾酮保护神经元免受β-淀粉样蛋白的毒性，而在其他研究中，睾酮加剧了中风引起的损伤大小。雄激素的这种二元性背后的机制仍然不清楚。最近，我们的实验室报道，雄激素对ERK/MAPK和Akt信号通路产生相反的影响，这取决于膜雄激素受体(AR)或细胞内AR被激活。推而广之，我们假设雄激素可能以不同的方式影响细胞活性，这取决于激活的受体。在这里，我们发现二氢睾酮(DHT)保护原代培养的皮质星形胶质细胞免受与碘乙酸诱导的毒性相关的代谢和氧化损伤，而DHT-BSA，一种细胞不渗透的DHT类似物，优先靶向于膜AR，抑制Akt信号，增加caspase3/7活性，并促进碘乙酸诱导的细胞死亡。有趣的是，DHT-BSA还阻断了DHT和雌二醇的保护作用。总而言之，这些数据支持在给定的细胞或组织中存在两条潜在竞争的雄激素途径，这可能为深入了解雄激素治疗是有益还是有害的争议提供依据。
In the central nervous system, androgens can exert either protective or damage-promoting effects. For example, testosterone protects neurons against beta-amyloid toxicity, whereas in other studies, testosterone exacerbated stroke-induced lesion size. The mechanism underlying this duality of androgens is still unclear. Recently, our laboratory reported that androgens elicit opposite effects on the ERK/MAPK and Akt signaling pathways, depending on whether a membrane androgen receptor ( AR) or intracellular AR was activated. By extension, we hypothesized that androgens may affect cell viability differently depending on which receptor is activated. Here, we found that dihydrotestosterone ( DHT) protected primary cortical astrocytes from the metabolic and oxidative insult associated with iodoacetic acid-induced toxicity, whereas DHT-BSA, a cell impermeable analog of DHT that preferentially targets the membrane AR, suppressed Akt signaling, increased caspase 3/7 activity, and enhanced iodoacetic acid-induced cell death. Interestingly, DHT-BSA also blocked the protective effects of DHT and estradiol. Collectively, these data support the existence of two, potentially competing, pathways for androgens in a given cell or tissue that may provide insight into the controversy of whether androgen therapy is beneficial or detrimental.