Abstract
BackgroundMicroglia 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.MethodsA 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.ResultsClemastine 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.ConclusionsClemastine 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.
Highlights
Microglia activation is associated with the development of hypoxic–ischemic brain injury (HIBI)
Determining IL-1β, nod-like receptor protein 3 (NLRP3), and histamine H1 receptor (HH1R) protein expression levels in the corpus callosum by double labeling and Western blot analysis In the corpus callosum of the control rats, the interleukin1beta (IL-1β) and NLRP3 expression levels were detected in sporadic cells and confirmed to be microglial cells by double labeling with Iba-1 staining (Fig. 1a–i and k–s)
At 1 day following bilateral common carotid artery occlusion (BCCAO), the IL-1β and NLRP3 immunoreactivities were induced in numerous microglial cells (Fig. 1d–f and n–p) when compared with that of the controls (Fig. 1a–c and k–m)
Summary
Microglia activation is associated with the development of hypoxic–ischemic brain injury (HIBI). 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. Cardiac arrest can cause severe neurological damage that can lead to a long-term unconscious state, and hypoxic–ischemic brain injury (HIBI) is the main cause of this poor prognosis [1]. Neuroinflammation has been widely recognized as a possible pathological factor in ischemic–hypoxic white matter injury [6] because of its involvement in the activation of microglia and the release of cytotoxic compounds, such as cytokines and reactive oxygen species [7]. Proinflammatory cytokines target oligodendrocyte progenitor cells (OPCs) [8], whereas interleukin-1 beta (IL-1β) impedes OPC recruitment by inhibiting white matter repair and functional recovery [9]. Neuroinflammation inhibition may be an interesting therapeutic target for white matter damage. The inhibition of NLRP3 activation in microglia reduces IL-1β release and brain damage [13]
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