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Micro-Doses of DNP Preserve Motor and Muscle Function with a Period of Functional Recovery in Amyotrophic Lateral
Renjia Zhong1,2,3, Demi L A Dionela1, Nina Haeyeon Kim1
1Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL.
Objective:
Mitochondrial dysfunction is one of the earliest pathological events observed in amyotrophic lateral sclerosis (ALS). The aim of this study is to evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in an ALS mouse model to provide preclinical proof-of-concept evidence of using DNP as a potential therapeutic drug for ALS.
Methods:
hSOD1G93A mice were treated with 0.5-1.0 mg/kg DNP through daily oral gavage from presymptomatic stage or disease onset until 18 weeks old. Longitudinal behavioral studies were performed weekly or biweekly from 6 to 18 weeks old. In situ muscle contraction measurements in extensor digitorum longus muscles were conducted to evaluate the preservation of contractile force and motor unit numbers in hSOD1G93A mice following DNP treatment. Muscle innervation and inflammatory markers were assessed using immunostaining. Extent of protein oxidation and activation of Akt pathway were also examined.
Results:
DNP delayed disease onset; improved motor coordination and muscle performance in vivo; preserved muscle contractile function, neuromuscular junction morphology, and muscle innervation; and reduced inflammation and protein oxidation at 18 weeks old in hSOD1G93A mice. Strikingly, symptomatic hSOD1G93A mice exhibited a period of recovery in running ability at 20 cm/s several weeks after 2,4-dinitrophenol treatment started at disease onset, offering the first observation in disease phenotype reversal using a small molecule.
Interpretation:
Our results strongly support that micro-dose DNP may be used as a potential novel treatment for ALS patients, with a possibility for recovery, when used at optimal doses and time of intervention. ANN NEUROL 2025;97:542-557.
Insights
Micro-dose 2,4-dinitrophenol (DNP) shows promise for treating amyotrophic lateral sclerosis (ALS). This study found DNP improved motor function and reversed disease symptoms in an ALS mouse model, suggesting potential therapeutic benefits.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- Mitochondrial dysfunction is an early pathological hallmark of amyotrophic lateral sclerosis (ALS).
- Identifying effective therapeutic interventions for ALS remains a critical challenge.
Purpose of the Study:
- To evaluate the therapeutic efficacy of 2,4-dinitrophenol (DNP), a mild mitochondrial uncoupler, in a preclinical model of ALS.
- To provide proof-of-concept evidence for DNP as a potential treatment for ALS.
Main Methods:
- hSOD1G93A mice were treated with DNP from presymptomatic stages or disease onset until 18 weeks of age.
- Longitudinal behavioral assessments, in situ muscle contraction measurements, and histological analyses were performed.
- Evaluated muscle innervation, inflammatory markers, protein oxidation, and Akt pathway activation.
Main Results:
- DNP treatment delayed disease onset and improved motor coordination and muscle performance in vivo.
- Preserved muscle contractile function, neuromuscular junction integrity, and muscle innervation, while reducing inflammation and protein oxidation.
- Observed a notable recovery in running ability in symptomatic mice treated with DNP, indicating potential disease phenotype reversal.
Conclusions:
- Micro-dose DNP demonstrates potential as a novel therapeutic agent for ALS.
- Optimal dosing and timing of intervention may lead to recovery in ALS patients.
- These findings support further investigation of DNP for ALS treatment.
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