LB: Micro-dose 2,4-dinitrophenol preserves motor and muscle function in Amyotrophic Lateral Sclerosis hSOD1G93A mice


Pre-Clinical Research

Poster Number: T421


Renjia Zhong, PhD, University of Florida

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by motor neuron loss and muscle paralysis. In animal models, ALS is shown to initially occur at the neuromuscular junction (NMJ). Mitochondrial dysfunction is one of the main pathological manifestations that is commonly observed in ALS patients and almost all ALS animal models. Our preliminary study demonstrated that excessive mitochondrial Ca2+ uptake in skeletal muscle plays a primary role in ALS pathogenesis. Moreover, increased reactive oxygen species (ROS) production in the presynaptic component of the NMJ may contribute to the destruction of NMJ. Therefore, interventions that mitigate the excessive mitochondrial Ca2+ uptake and ROS production may serve as potentially effective treatments for ALS. 2, 4-dinitrophenol (DNP), a mild mitochondrial uncoupler, prevents neuronal loss, enhances motor coordination, and reduces oxidative stress in mouse models of several neurodegenerative diseases, when used at “micro-doses”. DNP was recently granted “Investigational New Drug” status by the FDA due to its neuroprotective effects. The purpose of this study was to evaluate the “disease-modifying” effects of DNP in a mouse model of ALS (hSOD1G93A) and to provide direct pre-clinical evidence for the use of DNP as a potential therapeutic drug for ALS. Our results showed that DNP treatment from 4 weeks old (early pre-symptomatic) at 0.5 or 1.0 mg/kg in hSOD1G93A mice delayed disease onset and improved motor coordination, muscle contractile function, NMJ morphology and muscle innervation at 18 weeks old. More importantly, the protective effect of DNP in NMJ and muscle structure and function persisted when starting treatment from disease onset (10 weeks old) at both 0.5 and1.0 mg/kg. This is of high clinical relevance as most of the ALS patients approach medical professionals after onset of symptoms. Our results overall support that micro-dose DNP may be used as a potential new treatment for ALS.