Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

Abstract

BackgroundSudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation.Methods and ResultsRats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation.ConclusionsTaken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.

Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice

“…Consistent with our findings, the combination of CQ and metformin resulted in CNS neuronal damage after cardiac arrest in rats [6]. We hope that our report will be helpful to stimulate…”

NLRP3 inflammasome-mediated microglial pyroptosis is critically involved in the development of post-cardiac arrest brain injury

“…These IL-1β and IL-18, in turn, propagate the neuroinflammatory response through further activation of resident cells (i.e., microglia) and recruitment of inflammatory cells, such as neutrophils, macrophages, and lymphocytes [40]. Given the over-activation of microglia and the increment in inflammatory cytokines after cardiac arrest as found in this and our previous studies [15,20,[42][43][44], we proposed that the overactivated microglia may undergo pyroptosis after cardiac arrest and aggravates the subsequent inflammation in the brain. Consistent with this hypothesis, our data demonstrate that there is indeed intensive pyroptosis and increased caspase-1 activity in the activated microglia population after cardiac arrest, along with Fig.…”

Involvement of AMP‐activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain

“…Metformin treatment for 3 weeks before permanent middle cerebral artery occulsion suppresses inflammation reaction (Zhu et al, 2015). Metformin treatment for 2 weeks before subjecting to 9 min asphyxia cardiac arrest (CA) ameliorates CA‐induced glial activation in the hippocampal CA1 region and cortex, which is accompanied by augmented AMPK phosphorylation and autophagy activation (Zhu et al, 2018). Not only metformin, but also other compounds which activate AMPK supress inflammation.…”

“…Further, acute metformin preconditioning activates AMPK and autophagy in the rat brain and reduces infarct bolume, neurological deficits and cell apoptosis during the focal cerebral ischaemia (Jiang et al, 2014). Also, Metformin treatment for 2 weeks before subjecting to asphyxia cardiac arrest (CA) ameliorates CA‐induced neuronal degeneration as well as glial activation in the rat hippocampal CA1 and cortex, which is accompanied by augmented AMPK phosphorylation and autophagy activation (Zhu et al, 2018). These metformin's effects are attenuated by an AMPK inhibitor (compound C) or an autophagy inhibitor (3‐methladenine) (Jiang et al, 2014).…”