Targeting Microglial Activation in Stroke Therapy: Pharmacological Tools and Gender Effects
Y. Chen, S.J. Won, Y. Xu and R.A. Swanson
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.
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.
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