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 SOD1G93A murine model of ALS.
Methodology/Principal Findings: Treatment of male and female SOD1G93A 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+/22 vs. 14+/22 motor units, p,0.005) and female TA muscles (21+/
21 vs. 15+/22 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 SOD1G93A 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/Significance: 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.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)