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Abstract
BackgroundAmyotrophic 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 FindingsTreatment 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+/−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 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/SignificanceThis 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.
Highlights
Amyotrophic Lateral Sclerosis (ALS [OMIM 105400]) is a fatal neurodegenerative disorder associated with the selective degeneration of upper and lower motor neurons, for which there are currently no effective therapeutics [1]
Metformin was originally prescribed for diabetes on the basis of its ability to reduce hepatic glucose production and increase insulin sensitivity [8], but it has subsequently been found to have potent anti-inflammatory [9,10,11] and antioxidant [11,12,13] properties as well as the ability to bring about mitochondrial biogenesis [14] and to cross the blood brain barrier (BBB) [15,16]
In order to investigate the potential of metformin treatment for the attenuation of pathology in SOD1G93A mice, we examined the effect of treatment of male and female SOD1G93A mice with 2 mg/ml metformin in the drinking water on motor unit survival in the right Tibialis Anterior (TA) and Extensor Digitorum Longus (EDL) muscles at 100 days of age
Summary
Amyotrophic Lateral Sclerosis (ALS [OMIM 105400]) is a fatal neurodegenerative disorder associated with the selective degeneration of upper and lower motor neurons, for which there are currently no effective therapeutics [1]. Metformin therapy has been successfully tested in mouse models of both Huntington’s disease (OMIM 143100) and multiple sclerosis (OMIM 126200), in which, like in ALS, inflammation, oxidative stress and mitochondrial defects are thought to be contributing factors to pathology [17,18] oral administration of metformin has been shown to increase lifespan and improve motor performance in male mice in the R6/2 model of Huntington’s disease [16] and to attenuate pathology and inhibit the expression of pro-inflammatory mediators in the murine Experimental Autoimmune Encephalomyelitis (EAE) model of multiple sclerosis [19]. 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 hypothesized that it might increase survival in the SOD1G93A murine model of ALS
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