通过 CX43/AQP4 轴阻断星形胶质细胞中的 p38MAPK 可减轻栓塞性中风小鼠模型的脑损伤。

IF 2 4区医学 Q3 NEUROSCIENCES

Journal of Stroke & Cerebrovascular Diseases Pub Date : 2024-10-10 DOI:10.1016/j.jstrokecerebrovasdis.2024.108085

Weiping Chen , Zhiping Wu , Min Yin , Yangbo Zhang , Yiren Qin , Xu Liu , Jianglong Tu

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引用次数: 0

摘要

背景：脑水肿是急性缺血性脑卒中（IS）引起的重要并发症，对发病率和死亡率有着至关重要的影响。p38MAPK已被证明可促进神经元凋亡和脑损伤。然而，p38MAPK抑制剂SKF-86002在防止缺血性损伤和脑水肿方面的作用仍不清楚：方法：用 TTC 染色法检测大脑中动脉闭塞（MCAO）小鼠的梗死面积。方法：通过 TTC 染色检查大脑中动脉闭塞（MCAO）小鼠的梗死面积，评估神经评分和脑水含量。TUNEL和NeuN染色用于评估神经元凋亡和神经元存活情况。血脑屏障（BBB）通透性由伊文思蓝测定。双重免疫荧光染色检测了星形胶质细胞中 AQP4 和 CX43 的共定位。IHC 染色显示了 CX43 和 AQP4 的表达。EDU 染色检测了氧和葡萄糖剥夺/复氧（OGD/R）处理的星形胶质细胞的增殖情况。使用商业试剂盒测定氧化应激标记物的水平。ELISA 用于评估促炎因子的分泌。RT-qPCR 检测了 CX43、AQP4 和促炎因子的表达。Western 印迹分析了 p-p38/p38、AQP4 和 CX43 的水平。共免疫沉淀（Co-IP）确定了 CX43 和 AQP4 之间的相互作用：结果：SKF-86002减轻了MCAO小鼠的脑损伤、水肿和神经元凋亡。SKF-86002抑制了星形胶质细胞的增殖，减轻了氧化应激和炎症反应。SKF-86002 可负向调节 p38 信号以及 AQP4 和 CX43 的表达。此外，SKF-86002还调节了星形胶质细胞内CX43/AQP4的表达：总之，SKF-86002可通过抑制星形胶质细胞增殖、氧化应激和炎症缓解IS损伤和脑水肿。这种效应与 CX43/AQP4 的抑制有关，表明 SKF-86002 有希望成为预防 IS 的新型治疗方法。

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Blockage of p38MAPK in astrocytes alleviates brain damage in a mouse model of embolic stroke through the CX43/AQP4 axis

Background

Cerebral edema, a significant complication arising from acute ischemic stroke (IS), has a critical influence on morbidity and mortality. p38MAPK has been shown to promote neuronal apoptosis and brain damage. However, the role of the p38MAPK inhibitor SKF-86002 in protecting against ischemic injury and cerebral edema remains unclear.

Methods

Infarct area was examined by TTC staining in middle cerebral artery occlusion (MCAO) mice. Neurological score and brain water content were evaluated. TUNEL and NeuN staining were used to assess neuronal apoptosis and the survival of neurons. Blood–brain barrier (BBB) permeability was determined by Evans blue. Double immunofluorescence staining detected the colocalization of AQP4 and CX43 in astrocytes. IHC staining revealed CX43 and AQP4 expression. EDU staining detected the proliferation of Oxygen and glucose deprivation/reoxygenation (OGD/R)-treated astrocytes. Levels of oxidative stress markers were determined using commercial kits. ELISA was used to assess the secretion of pro-inflammatory factors. RT-qPCR measured the expression of CX43, AQP4 and pro-inflammatory factors. Western blot analyzed the levels of p-p38/p38, AQP4 and CX43. Co-immunoprecipitation (Co-IP) determined the interaction between CX43 and AQP4.

Results

SKF-86002 attenuated brain damage, edema, and neuronal apoptosis in MCAO mice. Astrocyte proliferation was suppressed, and oxidative stress and inflammation were alleviated by SKF-86002 treatment. SKF-86002 negatively regulated p38 signaling and the expression of AQP4 and CX43. Additionally, the expression of CX43/AQP4 within astrocytes was modulated by SKF-86002.

Conclusion

In summary, SKF-86002 alleviated IS injury and cerebral edema by inhibiting astrocyte proliferation, oxidative stress and inflammation. This effect was associated with the suppression of CX43/AQP4, suggesting that SKF-86002 shows promise as a novel therapeutic approach for preventing IS.

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来源期刊

Journal of Stroke & Cerebrovascular Diseases Medicine-Surgery

CiteScore

5.00

自引率

4.00%

发文量

583

审稿时长

62 days

期刊介绍： The Journal of Stroke & Cerebrovascular Diseases publishes original papers on basic and clinical science related to the fields of stroke and cerebrovascular diseases. The Journal also features review articles, controversies, methods and technical notes, selected case reports and other original articles of special nature. Its editorial mission is to focus on prevention and repair of cerebrovascular disease. Clinical papers emphasize medical and surgical aspects of stroke, clinical trials and design, epidemiology, stroke care delivery systems and outcomes, imaging sciences and rehabilitation of stroke. The Journal will be of special interest to specialists involved in caring for patients with cerebrovascular disease, including neurologists, neurosurgeons and cardiologists.