Microglia in the Pathophysiology of Hemorrhagic Stroke and the Relationship Between Microglia and Pain After Stroke: A Narrative Review

Abstract

Stroke is a leading cause of death worldwide, and about a quarter of stroke patients are dead within 1 month. The prognosis is even worse for those with hemorrhagic stroke because the 1-month mortality approaches 50%. Besides, most patients who survive experience complications such as nausea, vomiting, and chronic pain. These adverse experiences, especially the existence of chronic pain, can lead to a decline in the patient's quality of life. In order to improve the treatment and prognosis of hemorrhagic stroke, there is an urgent need to understand its pathophysiological mechanism as well as the chronic pain it induces. This paper reviews studies of the molecular mechanisms of hemorrhagic stroke, especially the activation of microglia and the relationship between microglia and pain after stroke, which could shed new light on hemorrhagic stroke treatment.

Unique features of central neuropathic pain in multiple sclerosis: Results of a cluster analysis

“…A sensory profile similar to that of Cluster 1 was reported for people with CNP due to other etiologies although not in all cases (e.gDefrin et al, 2001; Klit et al, 2011; Ofek & Defrin, 2007; Tuveson et al, 2009) and therefore may characterize a CNP subtype. MS lesions along the spinothalamic‐thalamocortical pathways, as well as in brain regions that receive their input, may lead to pathological processes in the vicinity of, and within, deafferented nociceptive neurons, and in turn, to CNP emergence (He et al, 2021; Poncet‐Megemont et al, 2019; Wu et al, 2013). Unexpectedly, however, poor pain inhibition did not characterize the CNP group in the cluster analysis, despite reports of poor inhibition among other CNP patients (Albu et al, 2015; Gruener et al, 2016, 2020; Naugle et al, 2020; Tuveson et al, 2009).…”

Microglial phagocytosis and regulatory mechanisms after stroke

“…Therefore, C3aR antagonists or knock-out were beneficial in mouse models of ischemia/reperfusion injury. 25 Targeted complement inhibition could salvage stressed neurons and inhibit neuroinflammation after ischemic stroke as shown by administration of B4Crry, a complement inhibitor, which prevented microglial activation and microglial phagocytosis of stressed but salvageable neurons guided by the complement opsonins. 26 "Don't eat me" signals: CD47 and sialic acid Neuronal cells in the ischemic brain can also express "don't eat me" signals to counterbalance the "eat me" signals, and mitigate potential phagocytic neuronal injury after stroke.…”

“…22 Upon binding with each other, the ITIM domain is phosphorylated and recruits and activates protein tyrosine phosphatases, such as SHP-1 and reverse the tyrosine phosphorylation of signaling proteins, such as Syk, induced by activating receptors to inhibit phagocytosis. 25 Evidence suggests that SIRP/ CD47 signaling may play a protective role after ischemic stroke as neurological deficits and neuronal apoptosis after focal cerebral ischemia were all attenuated in SIRPa deficient mice. 28 However, whether this protection is mediated by a reduction in phagocytosis by don't eat me signals warrants further investigation.…”

“…As for hemorrhagic stroke, microglia transform into inflammatory cells and the direct phagocytosis and the indirect effects of proinflammatory factors will destroy the vascular endothelium and aggravate the hemorrhagic injury. 25 In conclusion, microglia play a complicated role in both ischemic stroke and hemorrhagic stroke: they engulf dead neurons and neuronal debris to reduce inflammation, but also phagocytose salvageable neurons in the ischemic penumbra. The microglial response to stroke can be divided into an acute, subacute, and long-term response by time, and by the ischemic core or the peri-infarct region by location, which differentially affects their function.…”

“…Therefore, C3aR antagonists or knock-out were beneficial in mouse models of ischemia/reperfusion injury. 25 Targeted complement inhibition could salvage stressed neurons and inhibit neuroinflammation after ischemic stroke as shown by administration of B4Crry, a complement inhibitor, which prevented microglial activation and microglial phagocytosis of stressed but salvageable neurons guided by the complement opsonins. 26…”