Hytrin Nanoformulation Reduces Nitrated Synucleinopathy Through Chaperon-Mediated Autophagy

Abstract

The loss of dopaminergic neurons, majorly due to synucleinopathy, is the prime cause of Parkinson's disease (PD) progression. Like phosphorylated synuclein, nitrated synuclein also significantly contributes to Lewy body formation in the PD etiology. Therefore, an approach to reduce nitrated synuclein enlightens the way of PD treatment. Recently, hytrin has emerged as a neurotherapeutic agent that activates IDH2 in synucleinopathy alleviation. However, burst release kinetics hamper the therapeutic efficacy of hytrin. We included our reported hytrin-loaded polydopamine-serotonin nanoparticles and utilized them for the investigation of therapeutic efficacy and molecular insights of neuroprotective action in an in vivo PD model with the aim to improve the therapeutic efficacy of hytrin. The present study explored behavioral testing, immunohistochemistry, and protein expression analysis to understand the camouflaged role of IDH2 in the activation of chaperone-mediated autophagy in the reduction of nitrated synuclein. The nanoformulation exhibited a neuroprotective efficiency through improved behavioral changes against PD deficits. The neuroprotective action has been attributed to IDH2-mediated Hsc70/Lamp2a induction in the reduction of nitrated synuclein. This study revealed the hytrin nanoformulation effect in the activation of chaperone-mediated autophagy to alleviate nitrated synucleinopathy in PD treatment.