Sicurezza, tolleranza ed efficacia del microdosaggio cronico di psilocibina sulla funzione visiva nei topi ischemici

Ischemic stroke remains a leading cause of disability worldwide, frequently resulting in cognitive and sensory impairments, including visual deficits when the primary visual cortex (V1) is affected. Current treatments fail to directly address these impairments, emphasizing the need for innovative therapies. Psilocybin, a serotonin receptor agonist and psychoplastogen, has shown potential in enhancing neuroplasticity, reducing inflammation, and modulating neuronal networks. This study evaluated the therapeutic potential and safety of chronic psilocybin microdosing (0.05 mg/kg) in preclinical stroke models. Using a photothrombotic stroke model in C57/B6J and Thy-GFP mice, bilateral and unilateral V1 lesions were induced to simulate ischemic damage. Psilocybin was administered either for 30 days (starting 15 days post-stroke) or 45 days (starting 24 hours post-stroke). Behavioral assessments, including T-maze, Visual Cliff, Looming Test, and Cued Morris Water Maze, were performed to evaluate visual perception, cognitive function, and learning ability. Histological and ex vivo analyses assessed lesion volume, dendritic spine density, retinal layer thickness, microglial and astrocyte density, and peripheral inflammatory biomarkers and cytokine levels. Psilocybin-treated mice exhibited significant improvements in visual task performance, including enhanced visual depth discrimination, faster flight responses to visual stimuli, and improved spatial memory performance compared to saline-treated controls. These improvements were significant in mice starting the treatment for 45 days with psilocybin immediately post-stroke (24 hours), whereas delayed treatment (starting 15 days post-stroke) yielded reduced benefits. Histological analyses demonstrated reduced lesion volumes, increased dendritic spine density in perilesional areas, and preserved outer nuclear layer thickness in the retina ipsilateral to the stroke site, mostly in animals starting the treatment 24 hours post-stroke. These findings suggest that early and sustained psilocybin administration post-stroke supports neuroplastic and functional recovery. C57/B6J mice without ischemic lesions were used to evaluate the safety of the chronic treatment with microdoses of psilocybin. The treatment resulted safe and well-tolerated in both male and female animals. Plasma analyses revealed reduced peripheral inflammatory markers following treatment. However, no significant differences were observed in microglial or astrocytic density within the amygdala or hippocampus, indicating that psilocybin's effects are likely mediated through neuroplastic and anti-inflammatory mechanisms rather than cellular density changes in glial populations. Importantly, sex-specific behavioral responses were noted, with anxiolytic effects observed in males and anxiogenic effects in females, highlighting potential sex-dependent differences in psilocybin’s therapeutic effects.