Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion.

Publisher: SAGE Publications Country of Publication: United States NLM ID: 8112566 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-7016 (Electronic) Linking ISSN: 0271678X NLM ISO Abbreviation: J Cereb Blood Flow Metab Subsets: MEDLINE

Publication: 2016- : Thousand Oaks, CA : SAGE Publications
Original Publication: New York : Raven Press, c1981-

White Matter* ; Metformin*/pharmacology ; Metformin*/therapeutic use ; Metformin*/metabolism ; Diabetes Mellitus, Type 2*/complications ; Brain Ischemia*/metabolism ; Cognitive Dysfunction*/etiology ; Cognitive Dysfunction*/complications ; Dementia, Vascular*/metabolism ; Carotid Stenosis*/complications ; Carotid Stenosis*/drug therapy ; Carotid Stenosis*/metabolism; Mice ; Animals ; Disease Models, Animal ; Mice, Inbred C57BL

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.
Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Keywords: BCAS; VCID; cerebral hypoperfusion; metformin; white matter injury

9100L32L2N (Metformin)

Date Created: 20230513 Date Completed: 20231110 Latest Revision: 20240513

20240513

PMC10638997

10.1177/0271678X231175189

37177813