Tirzepatide mitigates Stroke-Induced Blood-Brain barrier disruption by modulating Claudin-1 and C/EBP-α pathways

Duozi Wang; Jianhong Wang; Binghu Li; Shu Yang; Fuqiang Guo; Bo Zheng; Jian Wang

doi:10.1186/s10020-025-01312-4

Molecular Medicine (Jul 2025)

Tirzepatide mitigates Stroke-Induced Blood-Brain barrier disruption by modulating Claudin-1 and C/EBP-α pathways

Duozi Wang,
Jianhong Wang,
Binghu Li,
Shu Yang,
Fuqiang Guo,
Bo Zheng,
Jian Wang

Affiliations

Duozi Wang: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Jianhong Wang: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Binghu Li: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Shu Yang: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Fuqiang Guo: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Bo Zheng: Department of Neurology, the Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital
Jian Wang: Department of Neurology, Ya’an Peoples Hospital

DOI: https://doi.org/10.1186/s10020-025-01312-4
Journal volume & issue: Vol. 31, no. 1
pp. 1 – 15

Abstract

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Abstract Background Stroke is a major cause of disability and mortality worldwide, with ischemic stroke (IS) being the most common form. The blood-brain barrier (BBB) plays a critical role in protecting the brain, and its dysfunction after stroke exacerbates neuronal damage. Therefore, restoring BBB integrity is a promising therapeutic strategy. Tirzepatide (TZP), a dual GLP-1 and GIP receptor agonist, has demonstrated neuroprotective effects, but its role in BBB restoration post-stroke remains unclear. Objective This study aims to evaluate the potential of TZP in preventing BBB dysfunction and restoring its integrity in ischemic stroke models. Methods Using a middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke, we assessed the effects of TZP on neurological deficits, BBB permeability, and the expression of tight junction (TJ) proteins, particularly Claudin-1. In vitro, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemic conditions. The involvement of C/EBP-α, a key transcription factor regulating TJ proteins, was also investigated. Results TZP treatment significantly improved neurological scores and reduced BBB permeability in MCAO mice. It also restored Claudin-1 expression, which was downregulated in stroke conditions. In vitro, TZP reduced endothelial permeability and enhanced Claudin-1 expression in OGD/R-treated HBMVECs. Silencing C/EBP-α abolished the protective effects of TZP on both BBB integrity and Claudin-1 expression, indicating that C/EBP-α signaling is crucial for TZP’s action. Conclusion TZP ameliorates BBB dysfunction and protects against ischemic stroke by activating C/EBP-α signaling and restoring Claudin-1-mediated tight junction integrity. These findings suggest that TZP holds promise as a therapeutic agent for stroke, offering a novel strategy for maintaining BBB function and reducing neuronal damage. Further studies are needed to explore the detailed mechanisms underlying TZP’s neuroprotective effects and its clinical potential in stroke therapy.

Published in Molecular Medicine

ISSN: 1076-1551 (Print); 1528-3658 (Online)
Publisher: BMC
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology; Science: Chemistry: Organic chemistry: Biochemistry
Website: https://molmed.biomedcentral.com

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