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Current Medicinal Chemistry
ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
VOLUME: 21
ISSUE: 19
DOI: 10.2174/0929867321666131228203906      Price:  $58









Targeting Microglial Activation in Stroke Therapy: Pharmacological Tools and Gender Effects

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Author(s): Y. Chen, S.J. Won, Y. Xu and R.A. Swanson
Pages 2146-2155 (10)
Abstract:
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.
Keywords:
Brain, corticosteroid, female, HDAC, inflammation, ischemia, minocycline, PARP.
Affiliation:
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.