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

Abstract

Background: 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. 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, 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. 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. 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. Conclusions: 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.

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

“…Double immunofluorescence staining has shown that NLRP3 and IL-1β expression levels which are localized in the astroglia activated after ischemia-hypoxia. Our previous research found that HH1R is associated with neuroinflammation [4]. The results showed that HH1R exists in the astrocytes and the expression levels of IL-1β and NLRP3 were decreased by clemastine (H1 receptor antagonist), but the expression of HH1R was unaffected and localized in the astrocytes.…”

“…Cardiac arrest can cause severe neurological damage that can result in a long-term unconscious state, and hypoxic-ischemic brain injury (HIBI) is the main cause of this poor prognosis [1]. The role of white matter injury in HIBI has attracted more attention, axonal hypomyelination is the pathological hallmark of HIBI [2][3][4].…”

“…Neuroinflammation has been widely recognized as a possible pathological factor in HIBI [5,6] because of its involvement in the secretion of inflammatory factors, such as IL-1β [7]. Our previous study showed that nod-like receptor protein 3 (NLRP3) inflammasome activation lead to excessive expression of IL-1β, resulting in axonal hypomyelination [4,8]. Astrocytes are crucial regulators of neuroinflammation in the injured central nervous system [9].…”

“…Clemastine, a first-generation histamine H1 receptor (HH1R) antagonist, is a promising drug in central nervous system diseases [13]. Our previous study showed clemastine can inhibit neuroinflammation and improve axonal hypomyelination [4]. Whether clemastine improves axonal hypomyelination in HIBI through the regulationof astrocytic autophagy is unclear.…”

Substantia nigra Smad3 signaling deficiency: relevance to aging and Parkinson’s disease and roles of microglia, proinflammatory factors, and MAPK

“…To investigate the effect of SIS3 and LPS on inflammatory response in microglia, SIS3 (2 μl in 6-well plates or 1 μl in 24-well plates) or vehicle (DMSO) was added to the primary microglial cell cultures after enriched microglia were cultured for 1 day [ 38 ]. The final concentration of SIS3 was 10 μM.…”