Hytrin loaded polydopamine-serotonin nanohybrid induces IDH2 mediated neuroprotective effect to alleviate Parkinson's disease.

Parkinson's disease (PD) is the second most neurodegenerative disease caused due to synucleinopathy leads to the death of dopaminergic and serotonergic neurons. The approach to reduce synucleinopathy paves the therapeutic way in PD management. Recent studies highlight anti-Parkinsonism effect of Hytrin that regulates energy homeostasis via activation of mitochondrial redox regulator; IDH2 leading to attenuation of synucleinopathy. However, the burst release kinetics of Hytrin restricts its therapeutic potential. Therefore, we aimed to improve Hytrin release kinetics through nanocarrier mediated delivery, replenish dopamine and serotonin by formulating Hytrin loaded polydopamine serotonin nanohybrid for PD protection. Present study also explores IDH2 mediated neuroprotective action in retardation of synucleinopathy for PD prevention. Nanoformulation has shown effective neurotherapeutic potential by improving Hytrin release profile in the reduction of PD symptoms in vitro and ex vivo. The neuroprotective effect has been attributed to IDH2 induction and alpha-synuclein reduction against rotenone insults. The direct physical interaction of IDH2 and alpha-synuclein, PD hallmark has been uncovered. The study divulges that the restorative effect of our nanoformulation significantly retards the PD deficits byinducing IDH2 mediated alpha-synuclein ubiquitination and proteasomal degradation pathway.