Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice
Anti-inflammatory effects of PJ34, a poly(ADP-ribose) polymerase inhibitor, in transient focal cerebral ischemia in mice
复制标题
DOI：
10.1038/sj.bjp.0706837
复制
发表时间：
2006-09-01
影响因子：
7.3
通讯作者：
Margaill, I.
中科院分区：
文献类型：
--
作者：
Haddad, M.;Rhinn, H.;Margaill, I.
背景与目的：聚（ADP-核糖）聚合酶（PARP）的激活在脑缺血期间是有害的。我们评估了脑缺血诱导的 PARP 激活对促炎介质合成的影响，包括细胞因子、肿瘤坏死因子-α (TNF-α) 和白细胞介素-6 (IL-6) 以及粘附分子、E-选择素和细胞间粘附分子-1 (ICAM-1)。 实验方法：用氯胺酮麻醉雄性瑞士小鼠，通过血管内闭塞左侧大脑中动脉 1 h 来诱导缺血。赛拉嗪。在缺血发作前15分钟和缺血发作后4小时腹腔内给予PARP抑制剂PJ34（1.25-25 mg kg (-1)）。缺血后6小时或24小时处死动物并取出脑组织进行分析。主要结果：缺血后6小时和24小时脑组织中的TNF-α蛋白增加。所有剂量的 PJ34 均能在 6 小时内阻断 TNF-α 的增加，并且 25 mg kg (-1) PJ34 的持续作用长达 24 小时。实时定量聚合酶链反应显示，PJ34 (25 mg kg (-1)) 在 6 小时时将 TNF-α mRNA 的增加减少了 70%。 PJ34 还阻止编码 IL-6 (-41%)、E-选择素 (-81%) 和 ICAM-1 (-54%) 的 mRNA 增加。缺血后24小时，PJ34（25 mg·kg(-1)）可减少梗塞体积（-26%）并改善神经功能缺损。结论和意义：PJ34抑制脑缺血引起的四种炎症介质mRNA的增加。 PJ34 的这种作用对神经保护的贡献仍有待阐明。
Background and purpose: Activation of poly(ADP-ribose) polymerase (PARP) is deleterious during cerebral ischemia. We assessed the influence of PARP activation induced by cerebral ischemia on the synthesis of proinflammatory mediators including the cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and the adhesion molecules, E-selectin and intercellular adhesion molecule-1 (ICAM-1).Experimental approach: Ischemia was induced by intravascular occlusion of the left middle cerebral artery for 1 h in male Swiss mice anaesthetized with ketamine and xylazine. The PARP inhibitor PJ34 (1.25-25 mg kg (-1)) was administered intraperitoneally 15 min before and 4 hours after, the onset of ischemia. Animals were killed 6 h or 24 h after ischemia and cerebral tissue removed for analysis.Key results: Ischemia increased TNF-alpha protein in cerebral tissue at 6 and 24 h after ischemia. All doses of PJ34 blocked the increase in TNF-alpha at 6 h and 25 mg kg (-1) PJ34 had a sustained effect for up to 24 h. Quantitative real time polymerase chain reaction showed that PJ34 (25 mg kg (-1)) reduced the increase in TNF-alpha mRNA by 70% at 6 h. PJ34 also prevented the increase in mRNAs encoding IL-6 (-41%), E-selectin (-81%) and ICAM-1 (-54%). PJ34 (25 mg kg(-1)) reduced the infarct volume (-26%) and improved neurological deficit, 24 h after ischemia.Conclusions and Implications: PJ34 inhibited the increase in the mRNAs of four inflammatory mediators, caused by cerebral ischemia. The contribution of this effect of PJ34 to neuroprotection remains to be clarified.