Daily intranasal Resveratrol-conjugated gold nanoparticles administration promotes neuroprotection and improves neurological outcome in the R6/2 mouse model of Huntington's disease.

Introduction: Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by excitotoxicity, mitochondrial dysfunction, and neuroinflammatory responses, including microglial activation. Among natural bioactive molecules, Resveratrol has demonstrated promising immunomodulatory and neuroprotective properties in preclinical models of various diseases and in clinical contexts. In this study, we investigated the neuroprotective and anti- inflammatory potential of intranasally delivered gold nanoparticles conjugated with Resveratrol in the R6/2 transgenic mouse model of HD. Methods: Transgenic mice received daily administration of Resveratrol-conjugated nanoparticles (0.1 mg/kg/day), starting at 5 weeks of age—corresponding to the early (prodromal) phase of the disease. Following sacrifice, neuropathological changes were assessed through histological and immunohistochemical analyses. Results: Treated mice exhibited increased survival rates and attenuated motor and cognitive impairments compared to vehicle-treated controls. Notably, key outcomes such as reduced striatal degeneration, fewer neuronal intranuclear inclusions, and an attenuated microglial response indicated a significant neuroprotective effect. Moreover, Resveratrol treatment was associated with higher levels of phosphorylated CREB and BDNF in medium spiny neurons, along with an overall reduction in neuroinflammatory markers.