Neuroprotective Activities of Sertraline, Tiagabine, and Bicifadine with Autophagy-Inducing Potentials in a 6-Hydroxidopamine-Treated Parkinson’s Disease Cell Model

Abstract

Parkinson’s disease (PD) is one of neurodegenerative diseases characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The development of a neuroprotective therapy is crucial for mitigating features and progression of PD. Since autophagy induction has recently emerged as a promising neuroprotective strategy, this study aimed to identify autophagy-inducing compounds and evaluate their neuroprotective activity. Among 3,200 compounds consisting of FDA-approved drugs or are under active development, 547 compounds targeting neurological diseases were filtered in, and three compounds (sertraline, tiagabine and bicifadine) were finally identified to exhibit the autophagy-inducing activity and also demonstrated the autophagy-dependent neuroprotective action by inhibiting the mammalian target of rapamycin (mTOR) in 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells. Furthermore, the analysis of neurochemical changes suggested that the ability of those compounds to restore the quantity of cellular neurotransmitters such as betaine, 5-hydroxyindoleacetic acid and kynurenine might be linked to their neuroprotective function. In conclusion, compounds like sertraline, tiagabine, and bicifadine that have the ability to induce autophagy and inhibit mTOR might be repurposed as PD treatment to protect the neuronal cells.