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image of Hydroxychloroquine Prevents High-altitude Cerebral Edema by Inhibiting Endothelial Claudin-5 Autophagic Degradation

Abstract

Background

High-altitude cerebral edema (HACE) is a serious condition caused by prolonged hypobaric hypoxia (HH). Autophagic degradation of Claudin-5 plays a crucial role in HH-induced blood-brain barrier (BBB) damage. Hydroxychloroquine (HCQ), a lysosomal inhibitor used in autophagy treatment, reduces inflammation and BBB damage in traumatic brain injury. However, its effectiveness in preventing HACE is still unknown.

Methods

C57BL/6J mice were treated with HCQ and exposed to HH for 24 hrs to study BBB integrity. We evaluated BBB disruption brain water content, Evans blue, and FITC-dextran assays. Changes in tight junctions (TJs) of cerebrovascular endothelial cells were analyzed using electron microscopy and immunofluorescence. Western blotting quantified autophagy protein levels in brain tissue. Hypoxia-mimetic models were used to explore HCQ's effects on TJs and BBB permeability, confirmed by various assays, including immunofluorescence, electron microscopy, and Western blotting.

Results

HCQ significantly mitigated rapamycin-induced autophagy and Claudin-5 degradation. Prolonged hypoxia exposure promoted lysosomal degradation of Claudin-5, increasing endothelial cell permeability. HCQ inhibited autophagy in bEnd.3 cells the PI3K-Akt-mTOR and Erk pathway, reducing hypoxia-induced Claudin-5 down-regulation. In mice, HH exposure increased brain autophagy, damaging the vascular endothelial TJs and subsequently increasing endothelial permeability. Pretreatment with HCQ significantly reduced the level of autophagy in the brains of HH-exposed mice, thereby mitigating the HH-induced damage to vascular TJs, alleviating the downregulation of Claudin-5, and enhancing endothelial integrity.

Conclusion

HCQ effectively prevented HACE by inhibiting HH-induced Claudin-5 membrane expression downregulation, thus mitigating BBB damage and brain water content increase in HH-exposed mice.

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2025-05-09
2025-09-08

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Hydroxychloroquine Prevents High-altitude Cerebral Edema by Inhibiting Endothelial Claudin-5 Autophagic Degradation
Bentham Science Publishers ; https://doi.org/10.2174/011570159X371235250417051313
/content/journals/cn/10.2174/011570159X371235250417051313
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  • Article Type:     Research Article
Keywords: Hydroxychloroquine ; autophagy ; high-altitude cerebral edema ; prolonged hypobaric hypoxia ; blood-brain barrier ; Claudin-5

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