A PROMISING DRUG CANDIDATE FOR PARKINSON'S DISEASE

摘要

The purpose of this study and report was to evaluate GM6 as a Parkinson's Disease (PD) drug candidate and the possible mechanism of action and pathways. We show that GM6 rescues in vitro survival of salsolinol-treated SH-SY5Y cells and rat cortical neurons treated with post-mortem CSP from PD (Parkinson's Disease) patients. We show that short-term GM6 treatment improves BDNF blood levels i PD patients. Additionally, GM6 completely or partially abrogated dysfunction in 2 in vivo PD mouse models (6-0HDA, MPTP), leading to improved motor performance and dopaminergic neuron survival in both models. We also identify PD-associated genes regulated by GM6. These genes were categorized with respect to 6 hypothesized mechanisms of action, including (1 ) attenutation of kinase dysfunction via LRKK2 down-regulation, (2) anticholinergic actions, (3) pro-GABAergic effects, (4) enhancement of GDNF activity through activation of a GRFAI-RET axis, (5) improved oxidative stress defenses and (6) blunting of free radical generation through decreased mitochondrial activity or abundance.