Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, 97239-3098, USA,
Transl Stroke Res. 2011 Sep;2(3):346-57. doi: 10.1007/s12975-011-0079-z. Epub 2011 Apr 15.
Male sex is a known risk factor in human stroke. However, the role of the cognate receptor for androgens-the androgen receptor (AR)-in stroke outcome remains unclear. Here, we found that AR mRNA is downregulated in the peri-infarct tissue of gonadally intact male mice subjected to middle cerebral artery occlusion (MCAO) and 6 h reperfusion. We then used genetically engineered mice overexpressing AR in brain (AR-Tg) to compare outcomes from MCAO in intact or castrated males and to evaluate the neuroprotective role of dihydrotestosterone (DHT) replacement in AR-Tg castrates. A further evaluation of AR overexpression in ischemic paradigms was performed using rat PC12 cells transfected with human AR and treated with oxidative and apoptotic stressors. We then studied the role of DHT in cultures overexpressing AR. Our results show (1) ischemia alters the expression of AR by decreasing AR mRNA levels, (2) AR overexpression is protective in vivo against MCAO in intact and castrated AR-Tg mice and in vitro against oxidative and apoptotic stressors in AR-PC12 cells, and (3) DHT does not enhance the protection triggered by AR overexpression in AR-Tg castrated mice nor in AR-PC12 cells.
男性性别是人类中风的已知风险因素。然而，雄激素的同源受体——雄激素受体（AR）——在中风结果中的作用仍不清楚。在这里，我们发现，在接受大脑中动脉闭塞（MCAO）和 6 小时再灌注的性腺完整雄性小鼠的梗死周围组织中，AR mRNA 下调。然后，我们使用在大脑中过表达 AR 的基因工程小鼠（AR-Tg）来比较完整或去势雄性小鼠的 MCAO 结果，并评估 DHT 替代物在 AR-Tg 去势雄性中的神经保护作用。使用转染了人 AR 的大鼠 PC12 细胞进行缺血模型中的 AR 过表达的进一步评估，并使用氧化和凋亡应激原进行处理。然后，我们研究了 DHT 在过表达 AR 的培养物中的作用。我们的结果表明：（1）缺血通过降低 AR mRNA 水平改变 AR 的表达；（2）AR 过表达在体内对完整和去势 AR-Tg 小鼠的 MCAO 具有保护作用，在体外对 AR-PC12 细胞的氧化和凋亡应激具有保护作用；（3）DHT 不能增强 AR-Tg 去势雄性小鼠或 AR-PC12 细胞中 AR 过表达引发的保护作用。
