Dataset Information

Clemastine improves hypomyelination in rats with hypoxic-ischemic brain injury by reducing microglia-derived IL-1? 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-1? (IL-1?), 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-1? and NLRP3 in the corpus callosum of BCCAO rats. Primary cultured OPCs treated with IL-1? 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-1? and NLRP3 upregulation. Clemastine could downregulate NLRP3 and IL-1? 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.

SUBMITTER: Xie D

PROVIDER: S-EPMC7023767 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Xie Di D Ge Xiaoli X Ma Yanli Y Tang Jialong J Wang Yang Y Zhu Yajie Y Gao Chengjin C Pan Shuming S

Journal of neuroinflammation 20200215 1

<h4>Background</h4>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.<h4>Methods</h4>A bilateral common carotid artery occlusion (BCCAO) rat model that re ...[more]

PMID: 32061255

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Project description:BackgroundReducing neuroinflammatory damage is an effective strategy for treating white-matter damage (WMD) in premature infants. Caffeine can ameliorate hypoxia-ischemia-induced brain WMD; however, its neuroprotective effect and mechanism against hypoxic-ischemic WMD remain unclear.MethodsWe used 3-day-old Sprague-Dawley rats to establish a model of cerebral hypoxia-ischemia-induced brain WMD after unilateral common carotid artery ligation and hypoxia exposure (8% O2 + 92% N2) for 2.5 h. Mechanism experiments were conducted to detect M1/M2 polarization and activation of microglia and NLRP3 inflammasome.ResultsCaffeine inhibited NLRP3 inflammasome activation, reduced microglial Iba-1 activation, inhibited microglia M1 polarization, and promoted microglia M2 polarization by downregulating CD86 and iNOS protein expression, inhibiting the transcription of the proinflammatory TNF-α and IL-1β, upregulating CD206 and Arg-1 expression, and promoting the transcription of the anti-inflammatory factors IL-10 and TGF-β. Importantly, we found that these caffeine-mediated effects could be reversed after inhibiting A2aR activity.ConclusionsCaffeine improved long-term cognitive function in neonatal rats with hypoxic-ischemic WMD via A2aR-mediated inhibition of NLRP3 inflammasome activation, reduction of microglial activation, regulation of the phenotypic polarization of microglia and the release of inflammatory factors, and improvement of myelination development.ImpactThe direct protective effect of caffeine on hypoxic-ischemic white-matter damage (WMD) and its mechanism remains unclear. This study elucidated this mechanism using neonatal rats as an animal model of hypoxia-ischemia-induced cerebral WMD. The findings demonstrated caffeine as a promising therapeutic tool against immature WMD to protect neonatal cognitive function. We found that caffeine pretreatment reduced WMD in immature brains via regulation of microglial activation and polarization by adenosine A2a receptor, thereby, providing a scientific basis for future clinical application of caffeine.

Project description:Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.

Dataset Information

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

Publications

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

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