Natural small molecule Isorhamnetin and its optimized derivatives for Parkinson's disease treatment by targeting TFEB-mediated autophagy.

Parkinson’s disease (PD) is the most widespread neurodegenerative disease, with an unspecified origin, majorly characterised by the presence of protein aggregates of SNCA within cytoplasmic inclusions known as Levy bodies (LB). The accumulation of LBs in PD leads to progressive neuronal loss in the substantia nigra of the brain (SNpc), which may even expand into the adjacent striatal neurons. Recent studies indicate that dysfunction in ALP is closely related to neurodegenerative diseases, especially PD. Hence, effective disease-altering and/or promising neuroprotective drugs which can ameliorate the disease progression are urgently required. The autophagy-lysosome pathway (ALP) is a highly conserved cellular catabolic process intended for the degradation of impaired cellular organelles and neurotoxic protein aggregates. Dysfunction of ALP by aggregate-prone proteins has been linked to several human diseases including neurodegenerative disorders. Recently, transcription factor EB (TFEB) was identified as a master regulator of autophagy and lysosomal biogenesis. Therefore, discovery and development of specific direct activators of TFEB is needed for future clinical application. Isorhamnetin, a metabolite of quercetin has been studied to possess several neuroprotective activities. Isorhamnetin shows anti-inflammatory and anti-oxidative activity in in vitro models, and also show neuroprotective effects on scopolamine-induced neuronal damage in in vivo mice models. These findings indicate that, isorhamnetin is an excellent candidate for anti-PD pharmaceutical research. However, its SNCA-reducing activity has not been explored in PD models and there apparently have been no attempts to modify the structure of isorhamnetin for further optimizing and enhancing its bioactivity. Since isorhamnetin has low water solubility and limited brain bioavailability, structural modifications should be possible to optimize isorhamnetin with enhanced physiochemical properties. In our study, we propose to modify the structure of isorhamnetin and optimize the solubility and brain bioavailability, and also enhance its neuroprotective activity in in vitro and in vivo PD models.