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The Protective Effects of Acetazolamide Against Homocysteine-Induced Blood–Brain-Barrier Disruption by Regulating the Activation of the Wnt/β-Catenin Signaling Pathway

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Abstract

Acetazolamide (AZA) is a carbonic anhydrase inhibitor (CAI) with neuroprotective effects. Hyperhomocysteinemia is associated with blood–brain-barrier (BBB) disruption in brain disorders. A previous study indicated that AZA might have a new role in brain disorders. However, its function in hyperhomocysteinemia-related BBB disruption has not been reported. Here, we aim to clarify the role of AZA in homocysteine (Hcy)-mediated BBB dysfunction using both in vivo and in vitro assays. We found that AZA improved memory and cognitive function, and reduced brain edema in Hcy-stimulated hyperhomocysteinemia model rats. This protective effect of AZA on hyperhomocysteinemia rats was accompanied by improved BBB permeability and increased expression levels of the tight junction proteins, occludin, and claudin-5. The in vitro assay results show that AZA prevented Hcy-induced cell injury and attenuated the increased permeability in Hcy-treated bEnd.3 brain endothelial cells. The Hcy-induced decrease in occludin and claudin-5, and increase in MMP-2 and MMP-9 expression levels were attenuated by AZA in bEnd.3 cells. Moreover, the Hcy-induced downregulation of the Wnt/β-catenin signaling pathway in bEnd.3 cells was abolished by AZA. Inhibition of Wnt/β-catenin by ICG-001 reversed the protective effects of AZA in Hcy-treated bEnd.3 cells. We also prove that this process is mediated by WTAP. These findings suggest that acetazolamide mitigated the Hcy-induced compromised brain vascular endothelial integrity by regulating the activation of the Wnt/β-catenin signaling pathway.

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Data Availability

Data of this study is available upon reasonable request to the corresponding authors.

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Acknowledgements

This work was supported by Medical Scientific Research Foundation of Guangdong Province (A2022491) and Climb Plan Foundation of Guangzhou Eighth People’s Hospital, Guangzhou Medical University.

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  1. Department of Neurology, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, No.8 Huaying Road, Guangzhou, 510440, Guangdong, China

    Chuo Li & Bo Zhang

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  1. Chuo Li
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  2. Bo Zhang
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Chuo Li made substantial contribution to experimental design and data analysis; Chuo Li and Bo Zhang made substantial contribution to investigation and data collection; Chuo Li drafted the manuscript. All authors have read and approved the manuscript.

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Correspondence to Chuo Li.

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Li, C., Zhang, B. The Protective Effects of Acetazolamide Against Homocysteine-Induced Blood–Brain-Barrier Disruption by Regulating the Activation of the Wnt/β-Catenin Signaling Pathway. Neurotox Res 40, 1261–1271 (2022). https://doi.org/10.1007/s12640-022-00551-1

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