Study | Mouse strain | Disease model | G | Starting age* | Met dose + Application | Study/Met duration | n per Group | Main findings |
---|---|---|---|---|---|---|---|---|
PARKINSON'S DISEASE | ||||||||
(45) | B6, Dat-Cre AMPKb1/2 KO | Day 20 + 22: MPTP: 30 mg/kg | M | 8–10 weeks | 100 mg/kg/day Drinking water | 27 days | n = 6–10 | Met decreases MPTP-induced loss of TH-positive neurons in ST but not SN and reduces astrogliosis Met induces AMPK phosphorylation in WT animals, although effects on TH-positive neurons are independent of AMPK-KO |
(46) | C57BL | Day 1+2: MPTP: 10 mg | M | ? 20–25 g | 150 mg/kg/day Metal probe | 7 days | n = 5 | Met has no effect on MPTP-induced loss of TH-positive neurons in SN but reduces levels of microglia marker Iba1 Reduces amount of dopamine in the striatum |
(47) | C57BL/6N | Day 7: MPTP: 15 mg/kg, 4x | M | 8 weeks | 200 or 400 mg/kg/day, Drinking water | 14 days | n = 3 /10 | Met reduces MPTP-induced loss of TH-positive neurons in SN Met induces pCreb and PGC1α in SN and ST |
(48) | C57BL/6 | Day 1–7: MPTP: 30 mg/kg | M | 10 weeks 20–25 g | 200 mg/kg/day Injection | 14 days Met: day 8–14 | n = 6 | Met ameliorates MPTP-induced motoric deficits Met decreases MPTP-induced loss of TH-positive neurons in SN and reduces astrogliosis Met induces AMPK and AKT phosphorylation, reduces levels of phosphorylated mTor and induces BDNF in the SN |
(49) | C57BL/6 | 5 weeks: every 3.5 day; MPTP: 20 mg/kg + 250 mg/kg probenecid | M | 10 weeks | 5 mg/ml Drinking water | 5 weeks Met: day 3–35 | n = 4–5 | Met decreases MPTP-induced loss of TH-positive neurons in SN and reduces levels of inflammatory cytokines |
(50) | Swiss Albino Mice | Day 1–5: MPTP: 25 mg/kg + 250 mg/kg probenecid | M | ? 22–25 g | 500 mg/kg/day Oral gavage | 21 days | n = 12 | Met improves regeneration of MPTP-induced motoric deficits Met decreases MPTP-induced loss of TH-positive neurons in SN and induces BDNF expression |
(51) | C57BL/6N | None | F | 10 weeks | A: 5 g/kg Diet B: 5 g/l Drinking water | A: 1 month B: 6 months | A: n = 20 B: n = 4 | Met reduces protein levels of phosphorylated α-Synuclein in mouse brains |
(52) | C57BL/6J | Day 1: MDMA 20mg/kg | M | 3 months | 200–400 mg/kg/day i.p. injection | 3/8 days Met: 400 mg day 1, 200 mg day 2+3 | n = 7–12 | Met reduces MDMA-induced loss of TH-positive neurons in SN and CPu |
ALZHEIMER'S DISEASE | ||||||||
(37) | P301S tau transgenic C57BL/6 | Transgenic, tau mutation | m | 4 weeks | 2 mg/ml Drinking water | 4 months | n = 12–15 | Met reduces Ser262-tau phosphorylation in CX and Hip but increases number of tau inclusions Met induces AMPK phosphorylation and PP2A protein levels and in CX and HIP |
(53) | db/db mice (BKS.Cg-m+/+ Leprdb/J) | Transgenic, leptin receptor mutation | M | 6 weeks | 200 mg/kg/day Oral gavage | 6 weeks | n = 3–10 | Met decreases 125I-Ab1−40 influx and RAGE expression at the BBB in db/db mice Met ameliorates memory impairments in db/db mice |
(54) | Wildtype | None | ? | ? | 5 mg/ml Drinking water | 16–24 days | n = 6 | Met reduces Ser202- and Ser262-tau phosphorylation in mouse brains |
(55) | db/db mice | Transgenic, leptin receptor mutation | m | 7 weeks | 200 mg/kg/day i.p. injection | 18 weeks | n = 6–11 | Met has no effect on spatial learning and memory Met reduces total tau protein levels as well as Ser396 phosphorylated tau in Hip and decreases JNK phosphorylation |
(56) | C57BL/6J | None | 5 weeks | 2 mg/ml Drinking water | 1 week | n = 4 | Met increases BACE-1 and APP protein levels and induces AMPK phosphorylation in mouse brains | |
COGNITION | ||||||||
(57) | C57BL/6 | HFD (60% fat) | M | 12 months | 1% Diet | 6 months | n = 16 | Met attenuates HFD-induced deficits in motor function and memory |
(58) | NIH Swiss mice | HFD (45% fat) | M | 6-8 weeks | 300 mg/kg BW Drinking water | 20 days | n = 10 | Met does not improve HFD-induced cognitive deficits and has no effect on astrogliosis |
(59) | Wistar rats | HFD (45% fat) | M | ? 125–150 g | 144 mg/kg Diet | 10 weeks | n = 16–24 | Met has no effect on HFD-induces deficits in Matching To Position Test |
(60) | Wistar rats | HFD (59.28% fat) | M | 6 weeks HFD 13 weeks Met | 15 mg/kg 2x/day Gavage feeding | 9 weeks HFD 3 weeks Met | n = 8 | Met reduces HFD-induced memory deficits Met reduces HFD-induced mitochondrial dysfunction |
(61) | C57BL/6J | None | M | 4/11/22 months | 2 mg/ml Drinking water | 3 months | n = 16–18 | Met has no effect or even impairs spatial memory |
HUNTINGTON'S DISEASE AND AMYOTROPHIC LATERAL SCLEROSIS | ||||||||
(62) | R6/2- B6CBAF1/J | Transgenic, huntingtin mutation (136-151 CAG repeats) | M/F | 5 weeks | 2 or 5 mg/ml Drinking water | Around 10 weeks (until death) | n = 5–9 | Met (2 mg) increases survival time in male mice but has no effect on female mice |
(63) | B6SJL-TgNSOD1G93A | Transgenic, SOD1 Mutation (G93A) | M/F | 5 weeks | 0.5 or 2 or 5 mg/ml Drinking water | Around 16 weeks (until death) | n = 6–15 | Met has negative effect on start of neurological symptoms and disease progression in female mice and has no effect in males |
Study | Disease | Characteristics | Result |
---|---|---|---|
(92) | PD | Retrospective cohort study, 800,000 individuals of whom 61,166 were diabetics, among the latter 41,003 received OAA therapy | Higher PD incidence for patients with T2DM without (HR 2.18) and with (HR 1.30) OAA compared to controls. HR for treatment with metformin alone was lower (0.95) than for sulfonylurea alone (1.57) and the combination showed the lowest HR (0.78) |
(93) | PD | Population-based retrospective cohort study with 93,349 T2DM patients receiving metformin (FU of 657,537 patient years) and 8,346 T2DM patients receiving glitazones with or without metformin (FU of 69,338 patient years) | Incidence of PD significantly lower in T2DM receiving glitazones compared to those receiving metformin (HR 0.72), no incident PD in long-term glitazone users who were still taking glitazones |
(94) | PD | Population-based retrospective cohort study with 41,362 patients receiving metformin alone, 316,210 patients receiving simvastatin alone, and 52,311 receiving both, metformin and simvastatin | Lower incidence of PD for patients receiving simvastatin alone (HR 0,64) or in combination with metformin (HR 0.74) compared to metformin alone |
(95) | PD/Dementia | Retrospective cohort study, 4,651 patients with T2DM with metformin treatment, 4,651 patients with T2DM with metformin treatment; >21,000 person-years of FU | Higher incidence density for PD (HR 2.27), AD (2.13), and VD (2.30) in the metformin group compared to those in the non-metformin group |
(96) | Dementia | Retrospective cohort study, 127,209 dementia-free individuals aged ≥50 years, of which 25,939 w/T2DM, 1,864 w/Metformin only, 9,257 w/Sulfonylureas + Metformin | Higher incidence of dementia in T2DM than controls, higher incidence in T2DM wo/ OAA compared to sulfonylurea (HR 0.85), metformin (HR 0.76), or a combination of metformin and sulfonylurea (HR 0.65) |
(97) | Dementia | 67,731 non-demented, nondiabetic individuals aged ≥65 years observed for 5 years and observation of onset of T2DM, antidiabetic medication and dementia | Increased risk of dementia onset for new-onset T2DM compared to non-T2DM (HR 1.56), risk to develop dementia was higher for thiazolidinedione users than for sulfonylurea and metformin |
(98) | Dementia | 189,858 individuals with 122,036 receiving metformin and 67,822 not receiving metformin, dementia incidence rate per 1,000 person-years | Patients with diabetes taking metformin had significantly lower dementia incidence rates than those not taking metformin (21.79 vs. 31.58 per 1,000 person-years, p < 0.001) |
(99) | Dementia | Meta-analysis including 544,093 participants, risk of dementia in patients with T2DM taking insulin sensitizers | Incidence of dementia reduced with metformin (RR 0.79) compared to those not taking insulin sensitizer but not significant (p = 0.064) |
(100) | Dementia | Latent class analysis to identify subgroups with differential effect of metformin on risk of age related comorbidities in 41,204 men with T2DM with 8,393 metformin users, | Identified 4 latent classes of patients who showed different effects of metformin on risk to develop ARC including dementia |
(101) | Dementia | Retrospective cohort study, 17,200 new metformin users vs. 11,440 new sulfonylurea users aged ≥65 years, average FU 5 years | Individuals <75 years of age on metformin had a lower risk to develop dementia than those on sulfonylurea (HR 0.67, 95% CI 0.61–0.73) |
(102) | Cognitive impairment | Longitudinal population-based study, 365 persons aged ≥55 years with T2DM of which 204 received metformin | Metformin use inversely associated with cognitive impairment (OR 0.49), longer use associated with lower risk of cognitive impairment |
(103) | AD | Retrospective case-control study, 7,086 AD patients and controls were compared for previous use of metformin/other antidiabetic drugs | Higher risk to develop AD for longterm users of metformin (AOR 1.71) but not sulfonylurea (AOR 1.01), thiazolidinediones (AOR 0.87), or insulin (AOR 1.01) compared to non-users |
(104) | AD | 71,433 patients newly diagnosed with diabetes and 71,311 nondiabetic controls, follow up of up to 11 years | Higher incidence of AD in diabetic patients compared to non-diabetics (0.48 vs. 0.38%), no positive effect of anti-hyperglycemic treatment on risk |
(105) | AD | Randomized placebo-controlled crossover study, 20 nondiabetic patients with MCI or mild dementia and AD received mg metformin or placebo for 8 weeks and then switched to the other treatment for 8 weeks | Metformin was measurable in CSF, in pooled post-hoc analysis significant increase in superior and middle orbitofrontal CBF after 8 weeks metformin exposure in ASL-MRI, significant improvement in Trail making test part B, a measure of executive function |
(106) | HD | Observational study; 4325 HD patients, of which 121 had T2DM and received metformin | HD patients on metformin fared better in test for verbal and executive function but not in motor assessments |