Metformin prevents brain injury after cardiopulmonary resuscitation by inhibiting the endoplasmic reticulum stress response and activating AMPK-mediated autophagy.

BACKGROUND AND AIMS: The neurological damage caused by cardiac arrest (CA) can seriously affect quality of life. We investigated the effect of metformin pretreatment on brain injury and survival in a rat CA/cardiopulmonary resuscitation (CPR) model.

METHODS AND

RESULTS

After 14 days of pretreatment with metformin, rats underwent 9 minutes of asphyxia CA/CPR. Survival was evaluated 7 days after restoration of spontaneous circulation; neurological deficit scale (NDS) score was evaluated at days 1, 3, and 7. Proteins related to the endoplasmic reticulum (ER) stress response and autophagy were measured using immunoblotting. Seven-day survival was significantly improved and NDS score was significantly improved in rats pretreated with metformin. Metformin enhanced AMPK-induced autophagy activation. AMPK and autophagy inhibitors removed the metformin neuroprotective effect. Although metformin inhibited the ER stress response, its inhibitory effect was weaker than 4-PBA.

CONCLUSION

In a CA/CPR rat model, 14-day pretreatment with metformin has a neuroprotective effect. This effect is closely related to the activation of AMPK-induced autophagy and inhibition of the ER stress response. Long-term use of metformin can reduce brain damage following CA/CPR.