Microglial Morphological Changes and Activation in Chronic Cerebral Hypoperfusion Are Suppressed by Lipid Peroxidation Inhibitor, Methyldopa

ABSTRACT Vascular dementia (VaD) is the second most common cognitive disease, and chronic cerebral hypoperfusion (CCH) is one of the causes of VaD. In CCH, neuroinflammation by immune cells in the brain is a key pathological feature in the development of VaD. However, it is unclear whether the cells contributing to disease pathogenesis during CCH are resident microglia (MG) or infiltrating monocyte‐derived macrophages (MΦs) owing to blood–brain barrier disruption. Therefore, we applied bilateral common carotid artery stenosis (BCAS) to Ccr2 RFP /+ ; Cx3cr1 GFP /+ mice capable of distinguishing between MG and MΦs and investigated MG activation and potential MΦs infiltration during disease progression. We discovered that MΦs did not infiltrate the brain up to four weeks after BCAS. In contrast, MG exhibited significant activation, predominantly to the pro‐inflammatory M1 phenotype. Additionally, methyldopa (MD), a compound we previously revealed to have lipid peroxidation (LPO) inhibitory property and which attenuated cognitive impairment in BCAS mice, reduced morphological changes and activation of MG during CCH. MD treatment decreased 4‐HNE‐modified proteins, indicating that LPO products contribute to neuroinflammation in CCH. These findings suggest that MG are activated prior to cognitive impairment by CCH and that LPO inhibitor can suppress MG activation, thereby attenuating pathological progression. image