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Updated: Jul 30, 2025
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Published on: April 23, 2021
Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion
Yixi He1,2, Zhenghao Li3, Xiaoyu Shi2
1Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
Insights
Metformin, a diabetes drug, alleviates white matter damage and cognitive impairment in a vascular cognitive impairment and dementia (VCID) mouse model. It restores oligodendrocyte precursor cell function by regulating hypoxia-inducible factor-1α.
Area of Science:
- Neuroscience
- Pharmacology
- Cerebrovascular Medicine
Background:
- Vascular cognitive impairment and dementia (VCID) presents significant treatment challenges.
- White matter integrity is crucial for cognitive function and susceptible to chronic hypoperfusion.
- Current treatments for VCID remain limited.
Purpose of the Study:
- To investigate the therapeutic potential of metformin in a mouse model of VCID.
- To elucidate the underlying mechanisms by which metformin affects white matter damage and cognitive function.
Main Methods:
- Establishment of a VCID mouse model using bilateral carotid artery stenosis (BCAS) to induce chronic hypoperfusion.
- Assessment of white matter damage and cognitive performance in metformin-treated and control mice.
- Investigation of metformin's effects on oligodendrocyte precursor cells (OPCs) under hypoxic conditions.
Main Results:
- Metformin treatment significantly alleviated white matter damage in the BCAS-induced VCID mouse model.
- Cognitive impairment was improved in mice treated with metformin.
- Metformin restored the function of OPCs under hypoxia by up-regulating prolyl hydroxylases 2, leading to HIF-1α degradation via AMPK activation.
Conclusions:
- Metformin demonstrates a promising therapeutic effect in ameliorating cognitive deficits associated with VCID.
- The drug's mechanism involves protecting white matter by restoring OPC function under hypoxic conditions.
- Metformin may represent a novel therapeutic strategy for treating VCID.
Abstract:
Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.
