title: Metformin treatment has no beneficial effect in a dose-response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice.
abstract: BACKGROUND
  Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motor neurons. The primary triggers for motor neuron degeneration are unknown but inflammation, oxidative stress and mitochondrial defects have been identified as potential contributing factors. Metformin is an anti-type II diabetes drug that has anti-inflammatory and anti-oxidant properties, can bring about mitochondrial biogenesis and has been shown to attenuate pathology in mouse models of Huntington's disease and multiple sclerosis. We therefore hypothesized that it might increase survival in the SOD1(G93A) murine model of ALS.
  
  
  RESULTS
  Treatment of male and female SOD1(G93A) mice (n = ≥6 per sex) with 2 mg/ml metformin in the drinking water from 35 days, resulted in a significant increase in motor unit survival, as measured by in vivo electrophysiology at 100 days, in male EDL muscles (24+/-2 vs. 14+/-2 motor units, p<0.005) and female TA muscles (21+/-1 vs. 15+/-2 motor units, P = 0.0134). We therefore continued to test the effect of 0.5, 2 and 5 mg/ml metformin in the drinking water from 35 days on disease onset and progression (identified by twice weekly determination of weight and neurological score) as well as survival in male and female SOD1(G93A) mice (n = ≥14 per sex). Results for all groups were compared using Kaplan-Meier time to event analyses. In this survival study, metformin was unable to reduce pathology at any dose and had an unexpected dose-dependent negative effect on the onset of neurological symptoms (P = 0.0236) and on disease progression (P = 0.0362) in female mice.
  
  
  CONCLUSIONS
  This study suggests that metformin is a poor candidate for clinical trial in ALS patients and that the possibility of harmful effects of metformin in female ALS patients with type II diabetes should be investigated.
authors: Wolfson Neuroscience Laboratories, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom.
authors: Hannah M
authors: HM
authors: Kaneb
authors: Paul S
authors: PS
authors: Sharp
authors: Nazanin
authors: N
authors: Rahmani-Kondori
authors: Dominic J
authors: DJ
authors: Wells
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D019943:Amino Acid Substitution / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008687:Metformin / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D008687:Metformin; D013482:Superoxide Dismutase