A new compound W026B alleviates ischemic brain injury through inhibiting the production of inflammatory cytokines in pMCAO and tMCAO, and enhances the beneficial effect of tPA

新化合物W026B通过抑制炎性细胞因子的产生减轻缺血性脑损伤,与tPA合用作用增强（英文）

Neruoprotection is considered as one of important therapeutic approaches for ischemic stroke.Inflammation plays an important role in the pathogenesis of ischemic stroke,and the inhibition of inflammation in the ischemic brain tissue may provide neuroprotective effect.In this study,we observed the influence of permanent middle cerebral artery occlussion（pMCAO） and transient MCAO（tMCAO） on NF-κB level and production of several inflammatory cytokines in injured hemisphere in mice,investigated the regulative effect of a new compound W026 B on these influences in the two MCAO models.In pMCAO model,10 μg/kg and 100 μg/kg of W026 B（i.v.） significantly reduced infarct volumes,100 μg/kg of W026 B significantly decreased neurologic deficit scores and brain water contents,and 10 μg/kg and 100 μg/kg of W026 B reduced Evans blue exudation from ischemic brain tissue.The level of NF-κB was elevated by 17.6 times in injured hemisphere,and the levels of TNF-α,IL-1β and IL-17 were elevated by 2.3 times,2.2 times and 3.8 times compared with the sham operation group,respectively,100 μg/kg of W026 B significantly reduced these inflammatory cytokines.In tMCAO model,the elevation of NF-κB,TNF-α,IL-1β and IL-17 was 2.3 times,1.4 times,1.5 times and 1.4 times compared with the sham operation group,respectively.Moreover,100 μg/kg of W026 B significantly decreased the levels of these inflammatory cytokines.In embolic MCAO mice model,W026 B alone significantly reduced infarct volumes,and combined application with tPA further reduced infarct volume.In conclusion,W026 B displayed significant protecive effect on three brain ischemia models.It could protect brain against injury induced by ischmia and ischemia-reperfusion through inhibiting the production of NF-κB,TNF-α,IL-1β and IL-17.These results suggest that W026 B has a value for further study.

神经保护被认为是缺血性脑卒中的重要治疗方法之一。炎症在缺血性脑卒中的发病机制中起着重要作用,抑制缺血性脑组织的炎症反应可能起到神经保护作用。本研究观察了新化合物W026B对小鼠永久性大脑中动脉阻塞模型(pMCAO)和短暂性大脑中动脉阻塞模型(tMCAO)的保护作用和对缺血侧脑组织NF-κB和一些炎性细胞因子表达的影响。在pMCAO模型中静脉注射W026B 10μg/kg和100μg/kg可明显减少小鼠缺血脑梗塞体积,100μg/kg W026B显著降低神经功能缺陷评分和脑含水量; 10μg/kg和100μg/kg W026B可减少血管内伊文思蓝渗出至缺血脑组织。与假手术组相比,缺血脑组织中细胞核内的NF-κB水平升高了17.6倍,组织中的TNF-α、IL-1β和IL-17分别升高了2.3倍、2.2倍和3.8倍,100μg/kgW026B可显著减少这些炎性细胞因子的水平。在tMCAO模型中,缺血组织中的NF-κB、TNF-α、IL-1β和IL-17的也分别升高2.3倍、1.4倍、1.5倍和1.4倍,100μg/kg的W026B也可显著减少这些炎性细胞因子的产生。在小鼠血栓栓塞e MCAO模型中W026B单独应用也可检索小脑梗死体积,与t PA联合应用作用增强。总之,W026B在三种脑缺血模型上均具有明显的保护作用,这些保护作用与其减少细胞核中的NF-κB的含量,减少TNF-α、IL-1β和L-17的产生有关。这些结果提示W026B可能具有进一步研究的价值。