Yang Shao-Hua, Liu Ran, Wen Yi, Perez Evelyn, Cutright Jason, Brun-Zinkernagel Anne-Marie, Singh Meharvan, Day Arthur L, Simpkins James W
Department of Pharmacology and Neuroscience, Health Science Center at Fort Worth, University of North Texas, Fort Worth, Texas 76107, USA.
J Neurobiol. 2005 Feb 15;62(3):341-51. doi: 10.1002/neu.20103.
Testosterone has been shown to exacerbate cerebral ischemia-reperfusion injury, which suggests that the well-known stress-induced testosterone reduction could be a protective response. We hypothesized that stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in male rats. In intact male rats, stress was induced by brief anesthesia at 6 h before transient middle cerebral artery occlusion (MCAO). Testosterone levels were significantly decreased 6 h after stress. Testosterone reduction was associated with a 50% reduction in cerebral lesion volume in the stressed animals. Further, the stress-induced cerebral ischemia tolerance was eliminated by testosterone replacement in castrated males. Immunohistochemical staining showed that androgen receptors were up-regulated after cerebral ischemia-reperfusion injury and partially colocalized with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells in the parietal cortex and extensively colocalized in the caudate putamen. Heat shock protein 70 (Hsp70) and 90 (Hsp90) are involved in ischemia tolerance, and were not colocalized with TUNEL in the immunohistochemical staining, suggesting an antiapoptotic role of Hsp's. To determine the effect of testosterone on MCAO-induced Hsp70 and -90 expression, a testosterone replacement or withdrawal paradigm was used. Testosterone-replaced animals exhibited a decrease in Hsp expression, whereas testosterone withdrawal (mimicking the stress-induced testosterone suppression) normalized this deficit. In summary, stress-induced testosterone reduction contributes to ischemia tolerance in cerebral ischemia-reperfusion injury in males, which could be related to the loss of inhibition by testosterone of Hsp70 and -90 expression.
睾酮已被证明会加剧脑缺血再灌注损伤，这表明众所周知的应激诱导的睾酮降低可能是一种保护反应。我们假设应激诱导的睾酮降低有助于雄性大鼠脑缺血再灌注损伤中的缺血耐受性。在完整的雄性大鼠中，在短暂大脑中动脉闭塞（MCAO）前6小时通过短暂麻醉诱导应激。应激后6小时睾酮水平显著降低。应激动物的睾酮降低与脑损伤体积减少50%相关。此外，去势雄性大鼠中睾酮替代消除了应激诱导的脑缺血耐受性。免疫组织化学染色显示，脑缺血再灌注损伤后雄激素受体上调，并且在顶叶皮质中部分与末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性细胞共定位，在尾状壳核中广泛共定位。热休克蛋白70（Hsp70）和90（Hsp90）参与缺血耐受性，并且在免疫组织化学染色中不与TUNEL共定位，表明热休克蛋白具有抗凋亡作用。为了确定睾酮对MCAO诱导的Hsp70和 -90表达的影响，采用了睾酮替代或撤药模式。睾酮替代的动物Hsp表达降低，而睾酮撤药（模拟应激诱导的睾酮抑制）使这种缺陷恢复正常。总之，应激诱导的睾酮降低有助于雄性大鼠脑缺血再灌注损伤中的缺血耐受性，这可能与睾酮对Hsp70和 -90表达的抑制作用丧失有关。
