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  3. Verapamil modulates astrocytic glycolytic dysfunction via TXNIP inhibition in the hippocampus of 3 × Tg-AD mice

Verapamil modulates astrocytic glycolytic dysfunction via TXNIP inhibition in the hippocampus of 3 × Tg-AD mice

  • Biochem Pharmacol. 2025 Aug 12;242(Pt 2):117233. doi: 10.1016/j.bcp.2025.117233.
Wenhui Zhou 1,  Xinyi Yin 1,  Jiayue Huang 1,  Li Fu 1,  Hanshika Yadav 1,  Wenjuan Yao 1,  Dandan Chu 2,  Feng Wu 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226019 Jiangsu, China.
  • 2 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
  • 3 Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226019 Jiangsu, China. Electronic address: wf619@ntu.edu.cn.
PMID: 40812585 DOI: 10.1016/j.bcp.2025.117233
Abstract

Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition marked by the accumulation of Amyloid-β plaques and a decline in cognitive abilities. Emerging research emphasizes astrocytic metabolic disturbances as contributors to AD development. This study investigates the therapeutic effects of Verapamil (VPM), a clinically approved Calcium Channel blocker, on astrocytic glycolysis in 3 × Tg-AD mice, focusing on the involvement of the thioredoxin-interacting protein (TXNIP)/glucose transporter 1 (GLUT1) pathway. VPM treatment significantly enhanced glycolytic activity in astrocytes, as evidenced by increased lactate production and improved metabolic function. Western blot and PCR analyses revealed a reduction in TXNIP levels and an upregulation of GLUT1 expression, particularly in the plasma membrane fraction, suggesting enhanced glucose uptake and glycolysis. Additionally, VPM treatment decreased soluble β-amyloid (Aβ) levels and alleviated cognitive impairments in the 3 × Tg-AD mice. These findings indicate that VPM restores glycolytic function in astrocytes through the TXNIP/GLUT1 pathway, offering a promising intervention targeting metabolic disruption and cognitive decline in AD. This study underscores the critical role of glycolysis in glial cells and highlights VPM's therapeutic potential in AD by targeting metabolic dysfunction.

Keywords

Alzheimer’s disease; Astrocytic glycolysis; GLUT1; TXNIP; Verapamil.

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