Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
ASN Neuro. 2011 Apr 7;3(2):e00056. doi: 10.1042/AN20100032.
Neuronal death pathways following hypoxia-ischaemia are sexually dimorphic, but the underlying mechanisms are unclear. We examined cell death mechanisms during OGD (oxygen-glucose deprivation) followed by Reox (reoxygenation) in segregated male (XY) and female (XX) mouse primary CGNs (cerebellar granule neurons) that are WT (wild-type) or Parp-1 [poly(ADP-ribose) polymerase 1] KO (knockout). Exposure of CGNs to OGD (1.5 h)/Reox (7 h) caused cell death in XY and XX neurons, but cell death during Reox was greater in XX neurons. ATP levels were significantly lower after OGD/Reox in WT-XX neurons than in XY neurons; this difference was eliminated in Parp-1 KO-XX neurons. AIF (apoptosis-inducing factor) was released from mitochondria and translocated to the nucleus by 1 h exclusively in WT-XY neurons. In contrast, there was a release of Cyt C (cytochrome C) from mitochondria in WT-XX and Parp-1 KO neurons of both sexes; delayed activation of caspase 3 was observed in the same three groups. Thus deletion of Parp-1 shunted cell death towards caspase 3-dependent apoptosis. Delayed activation of caspase 8 was also observed in all groups after OGD/Reox, but was much greater in XX neurons, and caspase 8 translocated to the nucleus in XX neurons only. Caspase 8 activation may contribute to increased XX neuronal death during Reox, via caspase 3 activation. Thus, OGD/Reox induces death of XY neurons via a PARP-1-AIF-dependent mechanism, but blockade of PARP-1-AIF pathway shifts neuronal death towards a caspase-dependent mechanism. In XX neurons, OGD/Reox caused prolonged depletion of ATP and delayed activation of caspase 8 and caspase 3, culminating in greater cell death during Reox.
缺氧缺血后神经元死亡途径存在性别二态性，但潜在机制尚不清楚。我们研究了雄性（XY）和雌性（XX）小鼠原代 CGN（小脑颗粒神经元）在 OGD（氧葡萄糖剥夺）后再氧合（Reox）期间的细胞死亡机制，这些 CGN 是 WT（野生型）或 Parp-1[多聚（ADP-核糖）聚合酶 1] KO（敲除）。将 CGN 暴露于 OGD（1.5 h）/Reox（7 h）中会导致 XY 和 XX 神经元死亡，但 XX 神经元在 Reox 期间的死亡更多。OGD/Reox 后，WT-XX 神经元中的 ATP 水平明显低于 XY 神经元；在 Parp-1 KO-XX 神经元中，这种差异消除了。AIF（凋亡诱导因子）仅在 WT-XY 神经元中从线粒体释放并转移到细胞核 1 小时。相比之下，WT-XX 和 Parp-1 KO 神经元中的 Cyt C（细胞色素 C）从线粒体释放；在这三个组中观察到延迟激活 caspase 3。因此，Parp-1 的缺失将细胞死亡转移到 caspase 依赖性细胞凋亡。OGD/Reox 后，所有组中还观察到 caspase 8 的延迟激活，但在 XX 神经元中更为明显，只有在 XX 神经元中，caspase 8 转移到细胞核。Caspase 8 的激活可能通过 caspase 3 的激活导致 Reox 期间 XX 神经元死亡增加。因此，OGD/Reox 通过 PARP-1-AIF 依赖性机制诱导 XY 神经元死亡，但 PARP-1-AIF 途径的阻断将神经元死亡转移到 caspase 依赖性机制。在 XX 神经元中，OGD/Reox 导致 ATP 的长时间耗竭和 caspase 8 和 caspase 3 的延迟激活，最终导致 Reox 期间更多的细胞死亡。
