BUBR1 Facilitated Nerve Regeneration by Modulating STAT3 Phosphorylation, Thereby Alleviating HIE in Neonatal Mice.

Abstract

Hypoxic-ischemic encephalopathy (HIE) represents a leading cause of morbidity and mortality among neonates. However, the underlying molecular mechanisms of HIE remain largely elusive. A HIE animal model was established, and neural stem cells (NSCs) underwent oxygen-glucose deprivation/reoxygenation (OGD/R) to mimic HIE in vitro. The HIE-induced brain injury was evaluated using a battery of assessments, including the Morris water maze test, wire hanging test, cylinder test, TTC, TUNEL, IHC, and IF staining. Subsequently, the expressions of budding uninhibited by benzimidazoles related 1 (BUBR1) and signal transducer and activator of transcription 3 (STAT3) were examined using immunoblotting and qRT-PCR. Furthermore, the interaction between BUBR1 and STAT3 was confirmed through co-immunoprecipitation assays. BUBR1 was observed to be downregulated in both the HIE model and in NSCs subjected to OGD/R. Notably, the restoration of BUBR1 expression was found to alleviate the detrimental effects of HIE, primarily by facilitating nerve regeneration. Further investigation revealed that BUBR1 also mitigated OGD/R-induced apoptosis in NSCs. Mechanistically, BUBR1 was shown to regulate the phosphorylation of STAT3, a crucial transcription factor involved in cell survival and regeneration. Moreover, BUBR1 alleviated OGD/R-induced apoptosis of NSCs and promoted nerve regeneration to protect HIE by regulating STAT3 phosphorylation. BUBR1 facilitated nerve regeneration by modulating STAT3 phosphorylation, thereby alleviating HIE.