BIOCHEMICAL MECHANISMS OF NEURONAL DEATH

越来越多的证据表明，聚（adp -核糖）聚合酶（PARP）的激活在缺血性脑损伤中起重要作用。然而，PARP神经毒性的机制尚未得到研究。基于有证据表明PARP产生的NAD+减少对线粒体通透性转变（MPT）和氧化应激的可能影响，本研究设计了实验来验证PARP刺激通过增强MPT和氧化损伤导致神经元死亡的假设。原代小鼠神经元单培养物被用作体外模型。PARP抑制剂和PARP基因破坏均可用于抑制PARP的激活。本研究可能提示兴奋性毒性和氧化性神经元死亡的新机制，并为减轻缺血性脑损伤提供新的见解。

A fast growing body of evidence suggests that poly(ADP-ribose) polymerase (PARP) activation plays an important role in ischemic brain damage. However, the mechanisms underlying PARP neurotoxicity remain unstudied. Based on the evidence suggesting the possible effects of a PARP-produced NAD+ decrease on mitochondria permeability transition (MPT) and oxidative stress, experiments are designed in this proposal to test the hypothesis that PARP stimulation elicits neuronal death by potentiating MPT and oxidative damage. Primary murine neuronal mono- cultures are used as in vitro models. Both PARP inhibitors and PARP gene disruption are used to depress PARP activation. This study may suggest novel mechanisms of excitotoxic and oxidative neuronal death, and provide new insights for attenuating ischemic brain damage.