Table 2:

Therapeutic effects and underlying mechanism(s) of action of metformin in experimental stroke models based on timing/duration of metformin treatment.

Mechanism of metformin	outcome	Timing/duration of metformin treatment	References
AMPK activation and AMPK-dependent M2 polarization of microglial cells	-Improved angiogenesis and neurogenesis -Functional recovery	Post- stroke chronic (30 days) treatment	[152]
AMPK activation, promoted eNOS phosphorylation	-Reduced ischemia-induced brain atrophy volume -Promoted focal angiogenesis and neurogenesis	Post- stroke (2 weeks) treatment	[121]
AMPK activation, modulating inflammatory and antioxidant pathways	-Attenuated cellular levels of NF-κB, TNF alpha and cyclooxygenase-2, -Increased levels of Nrf2 and heme oxygenase-1 -Enhanced levels of glutathione and catalase activities	Pre-treatment	[39]
AMPK activation	Chronic: -Improved stroke-induced lactate generation, -Imeliorated stroke-induced activation of AMPK Acute: -Increased infarct volume -Increased pAMPK levels	-Pre/Post-stroke chronic (3 weeks) treatment -Pre-stroke acute (3 days) treatment	[153]
AMPK activation	-Improved stroke-induced behavioral deficits -Enhanced angiogenesis	-Post-stroke chronic (3 weeks) treatment	[140]
AMPK phosphorylation, NF-κB inhibition, down-regulation of cytokines and ICAM-1 expression	-Reduced infarct volume -Improved neurobehavioral outcomes -Decreased BBB permeability	Post-stroke (2 weeks) treatment	[154]
Brain NF-κB suppression, reduction of pro-inflammatory cytokines and iNOS,	- Reduced infarct volume and improved neurological deficits -Ameliorated microgliosis and astrocytosis	Pre-treatment (3 weeks)	[147]
AMPK-dependent autophagy	Improved sensory motor signs Improved anxiolytic behavior and locomotion -Decreased autophagy factors	Pre-treatment (2 weeks)	[155]
improved the arterial baroreflex function, enhanced cholinergic anti-inflammatory pathway	-Up-regulation of vesicular acetylcholine transporter (VAChT) and α7nAChR - Down-regulated levels of pro-inflammatory cytokines	Pre-treatment (3 weeks)	[156]
AMPK activation	-Enhanced learning and memory -Improved neurological outcomes	Pre-treatment (2 weeks)	[157]
AMPK activation	-Attenuated apoptotic cell death - Induced mitochondrial biogenesis proteins	Pre-treatment (2 weeks)	[158]
Suppression of nitrotyrosine formation and nitration, improving Akt phosphorylation in endothelial cells, direct antioxidative effect	- Attenuated stroke-induced nitrative signaling -Improved angiogenesis -Prevented vasoregression-Improved functional recovery	Post-stroke (2 weeks) treatment	[143]
Activation of Akt1, reducing phosphorylation of JNK3 and c-Jun, elevation of cleaved caspase-3	Reduced cell apoptosis Attenuated the deficits of hippocampal related behaviors	Post-stroke (1 week) treatment	[142]
Pre- activation of AMPK - dependent autophagy	-Reduced infarct volume -Reduced neurological deficits -Reduced cell apoptosis	Pre-treatment (single dose)	[159]
Activation of peripheral AMPK	-Reduced ischemic neuronal damage -Decreased development of post-ischemic glucose intolerance	Post-stroke (1-3 days) treatment	[160]
Glycemic intervention	Improved neurovascular repair Improved functional outcome	Post-stroke (2 weeks) treatment	[161]
Glycemic intervention, AMPK activation and anti oxidative effects	-Reduced vascular remodeling -Reduced severity of hemorrhagic transformation -Decreased edema -Improved functional recovery	Post-stroke (4 weeks) treatment	[162]
Decreased expressions of total and phosphorylated AMPK	- Ameliorated brain infarct -Improved neurological scores -Reduced cell apoptosis	Pre-treatment (1 week)	[150]