Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, HRC-5N, Portland, OR 97239, USA.
Neuroscience. 2010 Mar 17;166(2):476-81. doi: 10.1016/j.neuroscience.2009.12.041. Epub 2009 Dec 24.
Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD(+)) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to wild type (WT) as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
聚（ADP-核糖）聚合酶（PARP）的激活会导致神经元烟酰胺腺嘌呤二核苷酸（NAD(+））耗竭、凋亡诱导因子的释放以及随后的胱天蛋白酶非依赖性细胞死亡，从而导致缺血性损伤。PARP 介导的细胞死亡存在性别二态性，参与雄性大脑的缺血性损伤，但不参与雌性大脑的损伤。我们检验了雄激素信号通路对于该雄性特有的神经元细胞死亡途径的必要性这一假说。与野生型（WT）相比，雄性 PARP-1 基因敲除（KO）小鼠在局灶性脑缺血（MCAO）后损伤较小，PARP 抑制剂 PJ34 处理的雄性小鼠损伤也减少。WT 小鼠中 PJ-34 提供的对缺血性损伤的保护作用在去势（CAST）后丧失，且雄激素替代可以恢复这种保护作用。与完整的雄性 KO 小鼠相比，CAST PARP-1 KO 小鼠的损伤增加，雄激素替代以雄激素受体依赖性的方式逆转了这种作用。最后，我们观察到缺血会导致 PARP-1 表达增加，而在缺乏睾丸雄激素的情况下，这种表达会减少。我们的数据表明，雄性大脑中 PARP 介导的神经元细胞死亡需要完整的雄激素-雄激素受体信号通路。
