Objective:

To systematically evaluate evidence linking oxidative stress to motor dysfunction in HD and assess the therapeutic potential of antioxidant strategies.

Background:

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG expansion in the HTT gene, leading to mutant huntingtin (mHTT) protein. Progressive motor dysfunction is a defining feature. Oxidative stress and mitochondrial dysfunction are increasingly recognized as key drivers of HD pathology.

Design/Methods:

A systematic search of PubMed and Google Scholar (2000–2024) was conducted using the terms “Huntington’s disease,” “oxidative stress,” and “antioxidants.” A total of 48 studies were screened, and 22 preclinical and 6 clinical studies that reported motor outcomes were included. Data were extracted on antioxidant interventions, motor performance, and survival.

Results:

Of the 22 preclinical studies, 18 reported improved motor performance or survival following antioxidant treatment (e.g., creatine, vitamin C, coenzyme Q10, curcumin, tauroursodeoxycholic acid, omega-3 fatty acids). In HD mouse models (R6/2, 3-NP), antioxidants reduced reactive oxygen species, preserved striatal neurons, and improved locomotion. In contrast, clinical trials with creatine and coenzyme Q10 in human HD patients failed to significantly alter disease progression, though mild symptomatic improvements were reported in small cohorts. Variability in study design, dosing, and endpoints limits direct comparison.

Conclusions:

Oxidative stress is a central driver of HD-related motor dysfunction. While antioxidants demonstrate robust neuroprotective effects in animal models, human clinical translation has been disappointing. These findings suggest that antioxidant monotherapy may be insufficient, and future strategies should focus on combination therapies that couple oxidative stress modulation with neurogenic and disease-modifying approaches.