Hydrogen mitigates brain injury by prompting NEDD4-CX43- mediated mitophagy in traumatic brain injury

IF 4.6 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2024-06-26 DOI:10.1016/j.expneurol.2024.114876

Fan Wu , Tao Liang , Yang Liu , Yongxing Sun , Baoguo Wang

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Abstract

Background

Hydrogen (H₂) has emerged as a potential therapeutic intervention for traumatic brain injury (TBI). However, the precise mechanism underlying H₂'s neuroprotective effects in TBI remain incompletely understood.

Methods

TBI mouse model was induced using the controlled cortical impact (CCI) method, and a cell model was established by exposing astrocytes to lipopolysaccharide (LPS). Cell viability was detected by CCK-8 kits. Cell apoptosis was measured by flow cytometry. ELISA was used to detect cytokine quantification. Protein and gene expression was detected by western blot and RT-PCR analysis. Co-immunoprecipitation (CO-IP) were employed for protein-protein interactions. Morris water maze test and rotarod test were applied for TBI mice.

Results

H₂ treatment effectively inhibited the LPS-induced cell injury and cell apoptosis in astrocytes. NEDD4 expression was increased following H₂ treatment coupled with enhanced mitophagy in LPS-treated astrocytes. Overexpression of NEDD4 and down-regulation of connexin 43 (CX43) mirrored the protective effects of H₂ treatment in LPS-exposed astrocytes. NEDD4 interacts CX43 to regulates the ubiquitinated degradation of CX43. While overexpression of CX43 reversed the protective effects of H₂ treatment in LPS-exposed astrocytes. In addition, H₂ treatment significantly alleviated brain injury in TBI mouse model.

Conclusion

H₂ promoted NEDD4-CX43 mediated mitophagy to protect brain injury induced by TBI, highlighting a novel pathway underlying the therapeutic effects of H₂ in TBI.

Abstract Image

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在创伤性脑损伤中，氢能通过促进 NEDD4-CX43 介导的有丝分裂减轻脑损伤。

背景：氢气（H2）已成为治疗创伤性脑损伤（TBI）的一种潜在干预措施。然而，氢气对创伤性脑损伤神经保护作用的确切机制仍不完全清楚：方法：采用可控皮质冲击（CCI）法诱导 TBI 小鼠模型，并通过将星形胶质细胞暴露于脂多糖（LPS）建立细胞模型。细胞活力由 CCK-8 试剂盒检测。细胞凋亡用流式细胞术检测。ELISA 用于检测细胞因子的定量。通过 Western 印迹和 RT-PCR 分析检测蛋白质和基因表达。共免疫沉淀（CO-IP）用于检测蛋白质与蛋白质之间的相互作用。对创伤性脑损伤小鼠进行莫里斯水迷宫试验和旋转体试验：结果：H2 处理可有效抑制 LPS 诱导的星形胶质细胞损伤和细胞凋亡。HRS处理后，NEDD4的表达增加，同时LPS处理的星形胶质细胞有丝分裂吞噬作用增强。在暴露于 LPS 的星形胶质细胞中，NEDD4 的过表达和 connexin 43 (CX43) 的下调反映了 H2 处理的保护作用。NEDD4 与 CX43 相互作用，调节 CX43 的泛素化降解。过表达 CX43 逆转了 H2 处理对暴露于 LPS 的星形胶质细胞的保护作用。结论：H2能促进NEDD4-CX43的降解：结论：H2促进了NEDD4-CX43介导的有丝分裂，从而保护了TBI诱导的脑损伤，凸显了H2治疗TBI的新途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.