Clemastine Improves Hypomyelination in Rats with Hypoxic–Ischemic Brain Injury by Reducing Astroglia-Derived IL-1β via Autophagy

Background: Cardiac arrest can lead to a poor prognosis of the nervous system. Neuroinflammation plays an important role in hypoxic ischemic brain injury (HIBI). Regulation of inflammation via autophagy might be a suitable therapeutic target in HIBI. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated astrocytes via autophagy and improving axonal hypomyelination in HIBI. Methods: A bilateral common carotid artery occlusion (BCCAO) rat model that received continuous intraperitoneal injection (1 mg/kg) for 14 days was employed to elaborate the neuroprotection effects of clemastine. interleukin-1β (IL-1β), nod-like receptor protein 3 (NLRP3), histamine H1 receptor, autophagy related protein and OPCs differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of astrocytes and OPCs were used to explore the link between astrocytes activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher’s protected least significant difference test. Results: Clemastine treatment could reverse hypomyelination and restrain the upregulation of IL-1β and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1β showed failed maturation. Expression of LC3Ⅱ/Ⅰdecreased after astrocytic activation. Co-culture of astrocytes and OPCs with oxygen glucose deprivation treatment exhibited NLRP3/1β upregulation and PLP downregulation. Clemastine could downregulate NLRP3/1β and reverse hypomyelination by promoting the autophagy. Conclusions: Clemastine could improve axonal hypomyelination by inhibiting astrocytes activation via promoting the autophagy in BCCAO rats, thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.