Activation of AMP-activated protein kinase by metformin protects against global cerebral ischemia in male rats: Interference of AMPK/PGC-1α pathway

Abstract

Here, we have investigated the effect of metformin pretreatment in the rat models of global cerebral ischemia. Cerebral ischemia which leads to brain dysfunction is one of the main causes of neurodegeneration and death worldwide. Metformin is used in clinical drug therapy protocols of diabetes. It is suggested that metformin protects cells under hypoxia and ischemia in non-neuronal contexts. Protective effects of metformin may be modulated via activating the AMP activated protein kinase (AMPK). Our results showed that induction of 30 min global cerebral I/R injury using 4-vesseles occlusion model led to significant cell death in the rat brain. Metformin pretreatment (200 mg kg/once/day, p.o., 2 weeks) attenuated apoptotic cell death and induced mitochondrial biogenesis proteins in the ischemic rats, analyzed using histological and Western blot assays. Besides, inhibition of AMPK by compound c showed that metformin resulted in apoptosis attenuation via AMPK activation. Interestingly, AMPK activation was also involved in the induction of mitochondrial biogenesis proteins using metformin, inhibition of AMPK by compound c reversed such effect, further supporting the role of AMPK upstream of mitochondrial biogenesis proteins. In summary, Metformin pretreatment is able to modulate mitochondrial biogenesis and apoptotic cell death pathways through AMPK activation in the context of global cerebral ischemia, conducting the outcome towards neuroprotection.

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

“…In after stroke period, metformin prevents neurons from nitrative stress and restored angiogenic signalling in the brain 39. In addition, it has been demonstrated that metformin attenuates the neurological deficits in ischaemic cerebral injury 40, 41. And according to our results, metformin could enhance functional recovery in rat SCI model.…”

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

“…Once activated, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways, thus allowing for adaptive changes in growth and metabolism under low energy conditions 23. Emerging evidence indicates that AMPK can be activated by metformin in the brain, exerting a neuroprotective role in response to energy depletion through maintaining cellular energy homeostasis,24, 25, 26 promoting mitochondrial biogenesis,27 and increasing brain‐derived neurotrophic factor expression to promote neuronal survival 28. Recently, autophagy has been proposed as a downstream target of AMPK, and AMPK‐induced autophagy activation protects against ischemic injury to peripheral tissue injury29, 30, 31 as well as ischemic brain injury 32.…”

Pre-Treatment with Metformin in Comparison with Post-Treatment Reduces Cerebral Ischemia Reperfusion Induced Injuries in Rats

“…For example, Liu et al, [25] showed that metformin could promote focal angiogenesis and neurogenesis and reduce injury in mice after middle cerebral artery occlusion. Ashabi et al, [37] found that metformin pre-treatment is able to improve stroke signs in the rats with global cerebral ischemia. In another study, it has been reported that treatment with metformin 24h after stroke, decreases brain atrophy [22].…”

“…In previous studies, it has been documented that metformin through phosphorylation of AMPK causes downstream signaling pathways in neurons during oxidative stress and neurodegeneration [37,45]. Other reports demonstrated that AMPK is activated by metformin administration which in turn activates some pathway including, mitochondrial biogenesis, antioxidant enzymes and nuclear factor erythroid 2 related factor (Nrf2) [37,42].…”