Activation of the CD200/CD200R1 axis improves cognitive impairment by enhancing hippocampal neurogenesis via suppression of M1 microglial polarization and neuroinflammation in hypoxic-ischemic neonatal rats

Abstract

Following hypoxic-ischemic brain damage (HIBD), there is a decline in cognitive function; however, there are no effective treatment strategies for this condition in neonates. This study aimed to evaluate the role of the cluster of differentiation 200 (CD200)/CD200R1 axis in cognitive function following HIBD using an established model of HIBD in postnatal day 7 rats. Western blotting analysis was conducted to evaluate the protein expression levels of CD200, CD200R1, proteins associated with the PI3K/Akt-NF-κB pathway, and inflammatory factors such as TNF-α, IL-1β, and IL-6 in the hippocampus. Additionally, double-immunofluorescence labeling was utilized to evaluate M1 microglial polarization and neurogenesis in the hippocampus. To assess the learning and memory function of the experimental rats, the Morris water maze (MWM) test was conducted. HIBDleads to a decrease in the expression of CD200 and CD200R1 proteins in the neonatal rat hippocampus, while simultaneously increasing the expression of TNF-α, IL-6, and IL-1β proteins, ultimately resulting in cognitive impairment. The administration of CD200Fc, a fusion protein of CD200, was found to enhance the expression of p-PI3K and p-Akt, but reduce the expression of p-NF-κB. Additionally, CD200Fc inhibited M1 polarization of microglia, reduced neuroinflammation, improved hippocampal neurogenesis, and mitigated cognitive impairment caused by HIBD in neonatal rats. In contrast, blocking the interaction between CD200 and CD200R1 with the anti-CD200R1 antibody (CD200R1 Ab) exerted the opposite effect. Furthermore, the PI3K specific activator, 740Y-P, significantly increased the expression of p-PI3K and p-Akt, but reduced p-NF-κB expression. It also inhibited M1 polarization of microglia, reduced neuroinflammation, and improved hippocampal neurogenesis and cognitive function in neonatal rats with HIBD. Our findings illustrate that activation of the CD200/CD200R1 axis inhibits the NF-κB-mediated M1 polarization of microglia to improve HIBD-induced cognitive impairment and hippocampal neurogenesis disorder via the PI3K/Akt signaling pathway.

Keywords: CD200; CD200R1; Hypoxic-ischemic brain damage; Neurogenesis; Neuroinflammation; PI3K/Akt.