Table 1.

Different cellular pathways studied on cultured neurons using metformin in vitro/in vivo model.

Biomodel	Culture	Effects	Postulated mechanism	Doses	Ref
Rat	Culture of primary neurons of day 17	Antiapoptotic	Pore opening inhibits mitochondrial permeability transition	100 μg for 24 hours	[25]
Mice	Immunostaining hippocampal sections	Neurogenesis	Metformin activates the aPKC-CBP pathway in neurons and induces neurogenesis of human neurons in culture. In adult mice, it induces neurogenesis in the hippocampus and olfactory bulb. Spatial learning tests improved in mice	Daily injected metformin (200 mg/kg) and BrdU for 3 days, and then only metformin for 9 days	[70]
Rat	Culture of cortical neurons from embryos obtained on gestation day 17,5	Antiapoptotic	Decreases neuronal death, inhibits apoptosis activation, maintains the mitochondrial gradient, inhibits cytochrome c release, and regulates internal calcium homeostasis	Culture at a high concentration of ethanol and groups received metformin (100 mM) and/or thymoquinone	[68]
Rat	Primary cultures of rat brain endothelial cells	Maintained integrity of BBB	Decreases sodium pass and maintains transmembrane electric gradient	Metformin dissolved 1 mM	[61]