Kauppinen Tiina M, Suh Sang Won, Berman Ari E, Hamby Aaron M, Swanson Raymond A
Department of Neurology, University of California San Francisco, San Francisco, California 94121, USA.
J Cereb Blood Flow Metab. 2009 Apr;29(4):820-9. doi: 10.1038/jcbfm.2009.9. Epub 2009 Feb 4.
The brain inflammatory response induced by stroke contributes to cell death and impairs neurogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kappaB and required for NF-kappaB-mediated inflammatory responses. Here we evaluated PARP inhibition as a means of suppressing post-stroke inflammation and improving outcome after stroke. Rats were subjected to bilateral carotid occlusion-reperfusion, and treatment with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) was begun 48 h later. PJ34 was found to rapidly suppress the ischemia-induced microglial activation and astrogliosis. Behavioral tests performed 6 to 8 weeks after ischemia showed deficits in spatial memory and learning that were lessened by the PJ34 treatment. Immunohistochemical evaluation of hippocampus at 8 weeks after ischemia showed increased neuronal density in CA1 layer of PJ34-treated animals relative to vehicle-treated animals. Bromodeoxyuridine labeling showed formation of new neurons in hippocampal CA1 area in PJ34-treated animals, but not in vehicle-treated animals. Together, these results suggest that treatment with a PARP inhibitor for several days after ischemia enhances long-term neuronal survival and neurogenesis by reducing inflammation.
中风引发的脑部炎症反应会导致细胞死亡并损害神经发生。聚（ADP - 核糖）聚合酶 - 1（PARP - 1）是转录因子NF - κB的共激活因子，是NF - κB介导的炎症反应所必需的。在此，我们评估了PARP抑制作为抑制中风后炎症和改善中风后预后的一种手段。对大鼠进行双侧颈动脉闭塞 - 再灌注，48小时后开始用PARP抑制剂N - （6 - 氧代 - 5,6 - 二氢菲啶 - 2 - 基） - N，N - 二甲基乙酰胺（PJ34）进行治疗。发现PJ34能迅速抑制缺血诱导的小胶质细胞激活和星形胶质细胞增生。缺血后6至8周进行的行为测试表明，PJ34治疗减轻了空间记忆和学习方面的缺陷。缺血后8周对海马体进行免疫组织化学评估显示，与接受载体治疗的动物相比，接受PJ34治疗的动物CA1层神经元密度增加。溴脱氧尿苷标记显示，接受PJ34治疗的动物海马体CA1区域有新神经元形成，而接受载体治疗的动物则没有。这些结果共同表明，缺血后用PARP抑制剂治疗数天可通过减轻炎症增强长期神经元存活和神经发生。
