Metformin regulates astrocyte autophagy via the AMPK/mTOR pathway to improve glutamate homeostasis and prevent cognitive impairment induced by cerebral ischemia-reperfusion
Abstract
IntroductionCerebral ischemia-reperfusion injury frequently causes cognitive dysfunction, and glutamate excitotoxicity induced by astrocyte overactivation is a core pathological mechanism. Autophagy exerts a critical regulatory effect on astrocyte function. This study aimed to investigate the preventive and protective effect of metformin (Met) against cerebral ischemia‐reperfusion‐induced cognitive impairment, and to elucidate how Met modulates astrocyte autophagy and glutamate homeostasis.MethodsIn vivo, a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model was established; in vitro, an oxygen‐glucose deprivation/reoxygenation (OGD/R) injury model was constructed using U251 human astrocytoma cells. Each model included control, injury, Met treatment, and intervention groups co‐treated with AMPK inhibitor Compound C or autophagy inhibitor chloroquine. Cognitive function was assessed via behavioral tests. Pathological and ultrastructural alterations were examined by HE staining, Nissl staining and transmission electron microscopy. The expression and colocalization of GFAP, GLT‐1 and LC3B were detected by immunofluorescence. Western blot was performed to measure target protein levels, and hippocampal glutamate content was determined.ResultsMet significantly improved cognitive function in MCAO/R rats, alleviated pathological damage and neuronal ultrastructural injury, suppressed hippocampal astrocyte overactivation, upregulated GLT‐1 expression and reduced glutamate accumulation in hippocampal tissue. Meanwhile, Met activated the AMPK/mTOR pathway and promoted autophagic flux, and autophagic changes were colocalized with astrocytes; consistent results were verified in U251 cells. These protective effects were reversed by both AMPK inhibitor and autophagy inhibitor.DiscussionMet pretreatment enhances astrocyte autophagy by activating the AMPK/mTOR pathway, which further upregulates GLT‐1 expression and improves glutamate homeostasis, ultimately ameliorating cerebral ischemia‐reperfusion‐induced cognitive dysfunction. These findings provide experimental evidence for the preventive and protective effects of Met against ischemic brain injury.
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BibTeX
@article{dong2026metformin,
title = {{Metformin regulates astrocyte autophagy via the AMPK/mTOR pathway to improve glutamate homeostasis and prevent cognitive impairment induced by cerebral ischemia-reperfusion}},
author = {Fei Dong and Zhi Ming and Yu Xiao and Yiwen Yu and Hao Zhao and Biao Li and Dong Lei and Qiuling Li and Shan Wang and Yifei Ji},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2010035},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2010035},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metformin regulates astrocyte autophagy via the AMPK/mTOR pathway to improve glutamate homeostasis and prevent cognitive impairment induced by cerebral ischemia-reperfusion
AU - Fei Dong
AU - Zhi Ming
AU - Yu Xiao
AU - Yiwen Yu
AU - Hao Zhao
AU - Biao Li
AU - Dong Lei
AU - Qiuling Li
AU - Shan Wang
AU - Yifei Ji
PY - 2026
DA - 2026/11/10
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2010035
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2010035
AB - IntroductionCerebral ischemia-reperfusion injury frequently causes cognitive dysfunction, and glutamate excitotoxicity induced by astrocyte overactivation is a core pathological mechanism. Autophagy exerts a critical regulatory effect on astrocyte function. This study aimed to investigate the preventive and protective effect of metformin (Met) against cerebral ischemia‐reperfusion‐induced cognitive impairment, and to elucidate how Met modulates astrocyte autophagy and glutamate homeostasis.MethodsIn vivo, a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model was established; in vitro, an oxygen‐glucose deprivation/reoxygenation (OGD/R) injury model was constructed using U251 human astrocytoma cells. Each model included control, injury, Met treatment, and intervention groups co‐treated with AMPK inhibitor Compound C or autophagy inhibitor chloroquine. Cognitive function was assessed via behavioral tests. Pathological and ultrastructural alterations were examined by HE staining, Nissl staining and transmission electron microscopy. The expression and colocalization of GFAP, GLT‐1 and LC3B were detected by immunofluorescence. Western blot was performed to measure target protein levels, and hippocampal glutamate content was determined.ResultsMet significantly improved cognitive function in MCAO/R rats, alleviated pathological damage and neuronal ultrastructural injury, suppressed hippocampal astrocyte overactivation, upregulated GLT‐1 expression and reduced glutamate accumulation in hippocampal tissue. Meanwhile, Met activated the AMPK/mTOR pathway and promoted autophagic flux, and autophagic changes were colocalized with astrocytes; consistent results were verified in U251 cells. These protective effects were reversed by both AMPK inhibitor and autophagy inhibitor.DiscussionMet pretreatment enhances astrocyte autophagy by activating the AMPK/mTOR pathway, which further upregulates GLT‐1 expression and improves glutamate homeostasis, ultimately ameliorating cerebral ischemia‐reperfusion‐induced cognitive dysfunction. These findings provide experimental evidence for the preventive and protective effects of Met against ischemic brain injury.
SN - 1663-9812
ER -