New Insights Into the Roles of Microglial Regulation in Brain Plasticity-Dependent Stroke Recovery

Abstract

Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.

Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice

“…There is still a lack of a specific antibody that recognize microglia and macrophages. Second, the distribution patterns of microglia are different between the brain of rodents and human [ 9 ], which may increase the difficulty of transforming basic research into clinical practice. Third, it is noteworthy that the activation of astrocytes contributes to neural injury after brain ischemia.…”

“…Microglia, the resident immune cells in CNS, can be activated rapidly after acute ischemic stroke and are responsible for brain damage, neuronal death and inflammatory response [ 9 ]. The patterns of microglial activation vary substantially between the infarcted core and peri-infarcted area [ 10 ].…”

The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke

“…The induction or promotion of the anti-inflammatory M2 microglia phenotype is one treatment strategy that has been employed in both preclinical and clinical studies to decrease inflammation in the acute and subacute phases and promote brain plasticity through in the chronic phase (113). Promotion of the M2 phenotype can be accomplished by administering molecular compounds which activate specific cell signaling pathways, such as the STAT3, AMPK, and PPARg pathways (140)(141)(142).…”

Changes in Brain Neuroimmunology Following Injury and Disease

“…They release VEGF, an angiogenic factor, to promote reformation of vasculature. Microglia also triggers expression of synaptic proteins and plays a role in neurogenesis, axonal regeneration, and other neural circuit recovery processes (Yu et al, 2021 ).…”