Dept. of Neurology, University of California San Francisco; and Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121, USA.
Curr Med Chem. 2014;21(19):2146-55. doi: 10.2174/0929867321666131228203906.
Ischemic stroke is caused by critical reductions in blood flow to brain or spinal cord. Microglia are the resident immune cells of the central nervous system, and they respond to stroke by assuming an activated phenotype that releases cytotoxic cytokines, reactive oxygen species, proteases, and other factors. This acute, innate immune response may be teleologically adapted to limit infection, but in stroke this response can exacerbate injury by further damaging or killing nearby neurons and other cell types, and by recruiting infiltration of circulating cytotoxic immune cells. The microglial response requires hours to days to fully develop, and this time interval presents a clinically accessible time window for initiating therapy. Because of redundancy in cytotoxic microglial responses, the most effective therapeutic approach may be to target the global gene expression changes involved in microglial activation. Several classes of drugs can do this, including histone deacetylase inhibitors, minocycline and other PARP inhibitors, corticosteroids, and inhibitors of TNFα and scavenger receptor signaling. Here we review the pre-clinical studies in which these drugs have been used to suppress microglial activation after stroke. We also review recent advances in the understanding of sex differences in the CNS inflammatory response, as these differences are likely to influence the efficacy of drugs targeting post-stroke brain inflammation.
缺血性中风是由大脑或脊髓血液流量严重减少引起的。小胶质细胞是中枢神经系统的固有免疫细胞，它们通过表现出激活表型来对中风做出反应，释放细胞毒性细胞因子、活性氧物质、蛋白酶和其他因子。这种急性先天免疫反应可能是从目的论上适应的，以限制感染，但在中风中，这种反应会通过进一步损害或杀死附近的神经元和其他细胞类型，并通过募集循环中的细胞毒性免疫细胞来加重损伤。小胶质细胞反应需要数小时到数天才能完全发展，这段时间间隔为启动治疗提供了一个临床可及的时间窗口。由于细胞毒性小胶质细胞反应存在冗余性，最有效的治疗方法可能是针对小胶质细胞激活所涉及的全局基因表达变化。几类药物可以做到这一点，包括组蛋白去乙酰化酶抑制剂、米诺环素和其他 PARP 抑制剂、皮质类固醇以及 TNFα 和清道夫受体信号的抑制剂。在这里，我们回顾了这些药物在中风后抑制小胶质细胞激活的临床前研究。我们还回顾了近年来对中枢神经系统炎症反应中性别差异的理解的最新进展，因为这些差异可能会影响针对中风后大脑炎症的药物的疗效。
