Targeting microglial activation in stroke therapy: pharmacological tools and gender effects.
Targeting microglial activation in stroke therapy: pharmacological tools and gender effects.
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DOI：
10.2174/0929867321666131228203906
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发表时间：
2014
影响因子：
4.1
通讯作者：
Swanson RA
中科院分区：
文献类型：
--
作者：
Chen Y;Won SJ;Xu Y;Swanson RA
缺血性中风是由流向大脑或脊髓的血液严重减少引起的。小胶质细胞是中枢神经系统的常驻免疫细胞，它们对中风的反应表现为激活的表型，释放细胞毒性细胞因子、活性氧物种、蛋白酶和其他因子。这种急性的、天生的免疫反应可能是为了限制感染而进行的目的性适应，但在中风中，这种反应可能会进一步损害或杀死附近的神经元和其他类型的细胞，并通过招募循环中的细胞毒性免疫细胞的渗透来加剧损伤。小胶质细胞的反应需要几个小时到几天的时间才能完全形成，这一时间间隔为临床开始治疗提供了一个时间窗口。由于细胞毒性小胶质细胞反应的冗余性，最有效的治疗方法可能是靶向参与小胶质细胞激活的整体基因表达变化。有几类药物可以做到这一点，包括组蛋白脱乙酰酶抑制剂，米诺环素和其他PARP抑制剂，皮质类固醇，肿瘤坏死因子α和清道夫受体信号的抑制剂。在这里，我们回顾了这些药物用于抑制中风后小胶质细胞激活的临床前研究。我们还回顾了在理解中枢神经系统炎症反应中的性别差异方面的最新进展，因为这些差异可能会影响针对中风后脑部炎症的药物的疗效。
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.
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