Quercetin Alleviates Demyelination Through Regulating Microglial Phenotype Transformation to Mitigate Neuropsychiatric Symptoms in Mice with Vascular Dementia

Cerebral hypoperfusion plays a pivotal role in the ictus and development of vascular dementia (VaD) with neuropsychiatric symptoms. To date, few pharmacological interventions for neuropsychiatric symptoms are available in the VaD patients with neuropsychiatric impairments. Here, our results demonstrated that the extent of demyelination was dramatically deteriorated and the thickness of myelin sheath was evidently decreased in the presence of cerebral hypoperfusion, whereas Quercetin possessed the potential of abrogating these effects at least in part, then relieving anxiety and depression-like behavior when mice exposed to bilateral carotid artery stenosis (BCAS)/chronic restraint stress (CRS). The underlying mechanism was that Quercetin facilitated secretion of anti-inflammatory cytokines (IL-4 and IL-10) and in turn decreased production of pro-inflammatory factors (TNF-α and IL-1β) due to regulating microglial phenotype transformation, thereafter enhancing the microglial engulfment ability of myelin fragments in vitro and in vivo. Collectively, the results demonstrated that that Quercetin mediated microglial transformation into anti-inflammatory phenotype to reduce demyelination in ventral hippocampus (vHIP), thereafter mitigating neuropsychiatric deficits (including anxiety and depression). The present research broadens the therapeutic scope of Quercetin in central nervous system (CNS) disorders with presence of white matter damage and/or the insufficient activation of anti-inflammatory microglia, particularly for vascular dementia with/without neuropsychiatric symptoms.