Hyperglycemia-induced endoplasmic reticulum (ER) stress and inflammatory response afflict neuropathological diseases (such as epilepsy and Alzheimer's disease). Astrocytes are the critical cells that mediate brain inflammation in this process. Metformin is a kind of hypoglycemic drugs widely used in clinical practice, which has anti-inflammatory and antioxidant effects. However, the biological mechanism of metformin in regulating inflammation and ER stress induced by hyperglycemia remains unclear. Therefore, in this study, rat primary astrocytes were preincubated with metformin and AMPK agonist AICAR for 1 h prior to administration of high glucose (33 mM glucose). Our findings indicated that metformin treatment inhibited the elevated ER stress and inflammation in high glucose-treated astrocytes. Moreover, metformin inhibited the formation of caveolin1/AMPK alpha complex. Additionally, the effects of AICAR on astrocytes were similar to metformin. In conclusion, metformin reduced high glucose induced ER stress and inflammation by inhibiting the interaction between caveolin1 and AMPK alpha, suggesting that the caveolin1/AMPK alpha complex may be a potential therapeutic target for metformin. (c) 2020 Published by Elsevier Inc.