Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway--do androgens matter?
Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway--do androgens matter?
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聚（ADP-核糖）聚合酶1引发了神经元细胞死亡途径 - 雄激素很重要吗？
DOI：
10.1016/j.neuroscience.2009.12.041
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发表时间：
2010-03-17
期刊：
影响因子：
3.3
通讯作者：
Herson, P. S.
中科院分区：
文献类型：
--
作者：
Vagnerova, K.;Liu, K.;Ardeshiri, A.;Cheng, J.;Murphy, S. J.;Hurn, P. D.;Herson, P. S.
聚（ADP-核糖）聚合酶的激活通过引起神经元NAD+耗竭、凋亡诱导因子的释放和随后的半胱天冬酶非依赖性细胞死亡而促成缺血性损伤。PARP介导的细胞死亡具有性别二态性，参与男性大脑的缺血性损伤，但不参与女性大脑。我们测试的假设，雄激素信号是需要这种男性特异性神经元细胞死亡途径。我们在雄性PARP-1敲除小鼠中观察到局灶性脑缺血（MCAO）后的损伤小于WT，并且在用PARP抑制剂PJ 34治疗的雄性小鼠中观察到损伤减少。PJ-34在WT小鼠中提供的缺血性损伤保护在去除睾丸雄激素（CAST）后丧失，并通过雄激素替代来挽救。与完整雄性KO小鼠相比，CAST PARP-1 KO小鼠表现出损伤增加，这一效应可通过雄激素受体依赖性方式的雄激素替代逆转。最后，我们观察到缺血导致PARP-1表达增加，而在睾丸雄激素缺乏的情况下，PARP-1表达减少。我们的数据表明，PARP介导的神经元细胞死亡在男性大脑中需要完整的雄激素-雄激素受体信号。
Activation of poly (ADP-ribose) polymerases contributes to ischemic damage by causing neuronal 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 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 indicates that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.
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