Table 1:

Effect of Metformin treatment in Neurodegenerative diseases in experimental animal models and cultured cells

Neurodegenerative disease	Description of study	Outcome(s)	References
Alzheimer’s disease	-Male db/db mice -200 mg/kg/day intraperitoneal metformin for 18 weeks	-Metformin mitigated the increase of total and phosphorylated tau and decreased the JNK activation. -Attenuated the reduction of synaptophysin	[77]
	-Primary cortical neurons and Neuro2a neuroblastoma cells treated with metformin	-Metformin significantly increased the generation of intracellular and extracellular AB species -Upregulated transcription of B-secretase (BACE1) -In combination with insulin, metformin enhances insulin’s effect in reducing AB level	[71]
	-In vitro model of “type 3 diabetes” -Differentiation of neuronal cell line Neuro-2a under prolonged presence of insulin and treatment with metformin	Metformin ameliorated neuronal insulin resistance Insulin sensitization by metformin prevented AD- associated neuropathological changes	[105]
	-db/db mice treated with 200 mg/kg metformin by oral gavage	-Metformin decreased AB influx across the BBB and decreased level of AB in hippocampus -Significant reduction of nuclear NF-kB p65 of brain microvessel endothelial cells -Suppression of caspase-3 activity and inhibited neuronal apoptosis	[106]
	-Primary cortical neurons treated with up to 2.5 mM metformin for 1-24 hours	-Metformin induces PP2A activity by inhibiting mTOR activity and reduces tau phosphorylation	[107]
	Human neural stem cells exposed to AB and treated with metformin	-Decreased Aβ-mediated mitochondrial deficiency -Significant restoration of mitochondrial morphology -Rescued cell viability through AMPK pathway activation	[108]
Parkinson disease	-Adult male swiss albino mice - Induction of parkinsonism in mice -Post metformin 500mg/kg treatment for 21 days	-Long-term metformin treatment resulted in significant improvement of the locomotor and muscular activities - Brain-derived neurotrophic factor significantly increased in metformin treatment group	[93]
	-Ten-week-old male C57BL/6 mice Induction of parkinsonism in mice Treatment with metformin 5mg/ml in drinking water for 5 weeks	Attenuated degeneration of substantia nigra compacta dopaminergic neurons by inhibiting microglial overactivation induced neuroinflammation Elevated striatal dopaminergic levels and improved motor impairment	[91]
	-10-week-old adult male C57BL/6 mice -MPTP injection (30 mg/kg/day) for the first 7 days to induce PD -Post metformin (200 mg/kg/day) for the next 7 days	-Metformin rescued tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. -Metformin restored dopamine depletion and behavioral impairments exerted by MPTP -Metformin ameliorated MPTP-induced synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to α-synuclein dephosphorylation	[109]
	-In-vitro pre-metformin treatment in SH-SY5Y cells	-Metformin’s AMP activation induced microtubule mediated autophagy and eliminated mitochondrial reactive oxygen species - Reduced MPP+ induced cytotoxicity and neuronal apoptosis	[91]
Multiple Sclerosis	- C57BL/6 J mice were administered with 0.2% cuprizone for 5 weeks for demyelination induction. -Post metformin treatment of 50 mg/kg/day for 1 weeks	-Increased localization of precursor oligodendrocytes and their renewal in the corpus callosum via AMPK/mTOR pathway -Reduced brain apoptosis markers and attenuated motor dysfunction	[110]
	Male C57BL/6 mice were fed with 0.2% cuprizone plus metformin by oral gavage of 100 mg/kg body weight in saline every day from day 0 until to the end of 6 weeks one time in a day	-The myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin -Metformin ameliorated the oxidative stress induced by cuprizone -Metformin upregulated expression of mitochondrial biogenesis genes -Metformin ameliorated the oxidative stress induced by cuprizone -Astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes	[111]
	-Female C57BL/6 wild-type mice, 8– 10 weeks of age -Induction of experimental autoimmune encephalomyelitis induced by subcutaneous injection of 250 μg of MOG35-55 peptide -100 mg/kg Metformin dissolved in saline solution was intraperitonially administered for 20 days	-Metformin reduced Th17 and increased Treg cell percentages along with the levels of associated cytokines -Metformin inhibited activation of mTOR and its downstream target, HIF-1α	[112]