Clemastine improves hypomyelination in rats with hypoxic-ischemic brain injury by reducing microglia-derived IL-1β via P38 signaling pathway

• Published in: Journal of neuroinflammation Vol. 17; no. 1; p. 57
• Main Authors: Xie, Di, Ge, Xiaoli, Ma, Yanli, Tang, Jialong, Wang, Yang, Zhu, Yajie, Gao, Chengjin, Pan, Shuming
• Format: Journal Article
• Language: English
• Published: England BioMed Central 15.02.2020; BMC
• Subjects: Brain injury; Brain research; Carotid artery; Cell culture; Cerebral blood flow; Clemastine; Corpus callosum; Cytokines; Extracellular signal-regulated kinase; Glial stem cells; Histamine H1 receptors; Hypomyelination; Hypoxia; IL-1β; Inflammation; Interleukin-1β; Ischemia; Kinases; Laboratory animals; Microglia; Neuroprotection; Oligodendrocyte; Progenitor cells; Proteins; Signal transduction; Therapeutic applications; Traumatic brain injury; United States > US; Clemastine; Hypomyelination; Oligodendrocyte; Interleukin-1β; Microglia
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-019-1662-6

Microglia activation is associated with the development of hypoxic-ischemic brain injury (HIBI). Neuroinflammation suppression might be a suitable therapeutic target in hypoxic oligodendrocyte injury. This study aims to determine whether clemastine can improve hypomyelination by suppressing the activated microglia and promoting the maturation of oligodendrocyte progenitor cells (OPCs) in HIBI. 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, and OPC differentiation levels in the corpus callosum were measured. Primary cultured OPCs and co-culture of microglia and OPCs were used to explore the link between microglia activation and hypomyelination. Data were evaluated by one-way ANOVA with Fisher's protected least significant difference test. 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. However, clemastine could also reverse the OPC maturation arrest by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Co-culture of microglia and OPCs with oxygen glucose deprivation treatment exhibited IL-1β and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1β and reverse hypomyelination by inhibiting the p38 signaling pathway. Clemastine could restrain microglia activation, improve axonal hypomyelination in BCCAO rats, and thus might be a viable strategy to inhibit hypomyelination in the corpus callosum of patients with HIBI.