Early Administration of Methylene Blue Attenuates Mitochondrial Dysfunction and Cognitive Deficits in a Model of Huntington’s Disease

Huntington’s disease (HD) is a fatal neurodegenerative disorder marked by progressive motor, cognitive, and psychiatric impairments, for which no disease-modifying therapies exist. Mitochondrial dysfunction is an early feature of HD, highlighting the need to target bioenergetic deficits early. We evaluated the neuroprotective effects of methylene blue (MB) in a 3-nitropropionic acid (3-NP)-induced HD-like rat model characterized by mitochondrial dysfunction and striatal injury. Male Wistar rats received MB for 14 days during 3-NP administration. Behavioral performance was assessed, followed by biochemical and histological analyses of the striatum. MB improved cognitive performance and partially improved specific aspects of motor coordination. At the mitochondrial level, MB restored Complex II activity, membrane potential index, reduced reactive oxygen species (ROS), and modulated mitochondrial function, but did not rescue Complex I. Histologically, MB attenuated striatal histopathological damage. These results suggest that methylene blue has neuroprotective effects in the early stages, particularly at the mitochondrial and cognitive levels. Its limited impact on other behaviors and systemic parameters could indicate that its efficacy depends on timing or duration. Overall, this study supports early mitochondrial targeting in HD therapy and shows methylene blue as a promising, though partial, disease-modifying candidate.