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Published on: December 15, 2023
Targeting microglial activation in stroke therapy: pharmacological tools and gender effects
1Dept. of Neurology, University of California San Francisco; and Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121, USA. raymond.swanson@ucsf.edu.
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.
Insights
Targeting microglial activation pathways offers a therapeutic window for ischemic stroke. Suppressing these immune responses may reduce brain damage and improve outcomes.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Ischemic stroke involves reduced blood flow to the brain, triggering a detrimental microglial immune response.
- Activated microglia release cytotoxic factors, exacerbating neuronal damage and recruiting peripheral immune cells.
- The development of microglial activation presents a therapeutic window for intervention.
Purpose of the Study:
- To review preclinical studies on drugs targeting microglial activation post-stroke.
- To explore therapeutic strategies aimed at suppressing detrimental neuroinflammation.
- To examine the influence of sex differences on CNS inflammatory responses and therapeutic efficacy.
Main Methods:
- Review of preclinical studies investigating drug interventions in ischemic stroke models.
- Analysis of drugs targeting global gene expression in microglial activation.
- Inclusion of research on sex differences in central nervous system (CNS) inflammation.
Main Results:
- Several drug classes, including HDAC inhibitors and minocycline, show potential in suppressing microglial activation.
- Targeting microglial pathways can mitigate secondary brain injury following ischemic events.
- Emerging evidence highlights significant sex-based variations in neuroinflammatory responses.
Conclusions:
- Modulating microglial activation is a promising therapeutic strategy for ischemic stroke.
- Drug development should consider sex differences to optimize treatment efficacy.
- Further research is needed to translate these preclinical findings into clinical practice.
