Table 2.

Different in vivo studies using metformin in a model of focal or global ischemia with or without reperfusion. Most of the studies show neuroprotective effects. PO: oral, IP: peritoneal injection, ICV: intraventricular, and IPC: ischemic preconditioning.

Biomodel	Strain	Ischemic focal or global	Time of ischemic/reperfusion	Neuroprotection	Postulated mechanism	Doses and route of administration✪	Metformin treatment time	Ref.
Rat	Wistar	Global	30 min/1 h	Yes	Reduction superoxide dismutase activity and glutathione peroxidase	500 mg/kg PO	One week before stroke	[57]
Rat	Sprague-Dawley	Focal	Not reperfusion	Yes	Suppression of the NF-κB inflammatory pathway	50 mg/kg IP	3 weeks before stroke	[71]
Mice	C57BL/6N	Focal	60 min/72 h	Yes	Angiogenesis and improve cerebral dopaminergic tone	0,2 mL/kg IP o 50 mg/kg/day IP	50 mg/kg/day beginning 24 h after stroke for 3 weeks	[72]
Rat	Sprague-Dawley	Focal	Not reperfusion	Yes	Induces autophagy	10 mg/kg/IP	Single dose 24 h before stroke	[73]
Mice	CD-1	Focal	90 min/14 days	Yes	Promotes neurogenesis and angiogenesis in subventricular zone	200 mg/kg IP	For 14 days after stroke	[74]
Rat	Goto-Kakizaki	Focal	90 min/14 days	Yes	Reduce levels of nitrotyrosine	300 mg/kg/day PO	For 14 days after stroke	[75]
Mice	C57BL/6N	Focal	3 min (IPC) at 72 hours 90 min/24 h	No	AMPK activation antagonizes neuroprotective effect of ischemic preconditioning	100 mg/kg IP	Single doses after stroke	[76]
Mice	CD-1	Focal	60 min/14 days	Yes	Favors change in phenotype M2 microglia/astrocyte	50 mg/kg/day IP	Beginning 24 h after stroke	[77]
Mice	C57BL/6	Focal	90 min/24 y 72 hours	No: acute treatment Yes: chronic treatment	In chronic treatment, less activation of AMPK	Acute: 50 a 100 mg/kg/día IP Chronic: 50 a 100 mg/k/day	Acute: 24 h before  Chronic: 3 weeks before	[39]
Rat	Wistar	Global	30 min/72 h	Yes	AMPK activation inhibits apoptosis in hippocampal neurons	200 mg/kg/day PO	2 weeks before ischemia	[69]
Rat	Goto-Kakizaki	Focal	90 min/21 h	Yes	Reduced vascular remodeling and severity of hemorrhagic transformation in diabetes	300 mg/kg/day PO	Starting with the onset of diabetes	[67]
Rat	Wistar	Global	30 min/72 h	Yes	Attenuates cellular levels of NF-kB and increased levels of Nrf2 in hippocampus	200 mg/kg/day PO	2 weeks before ischemia	[78]
Rat	Wistar	Global	30 min/72 h	Yes	Decreases reactive hyperemia and permeability of BBB in ischemic rats	200 mg/kg/day PO	2 weeks before ischemia	[62]
Mice	ddY	Focal	60 min/72 h	No: acute injection intraventricular Yes: chronic, IP	Central versus peripheral activation of AMPK	250 mg/kg/IP three times or 25,100 μg ICV three times for day	After stroke until death	[35]
Rat	Goto-Kakizaki	Focal	90 min/14 days	Yes	Improved vascularization in diabetic group, achieve euglycemia	300 mg/kg/day PO	After stroke until death	[66]
Mice	C57BL/6	Focal	60 min/24 h	Yes	In seven-day pretreatment, less activation of AMPK	10 mg/kg/day IP	After stroke until death	[79]