Neuroprotective effect of bicifadine, sertraline, and tiagabine with autophagy-inducing activity in 6-hydroxydopamine Parkinson’s models

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Neuronal cells, once impaired, do not undergo spontaneous regeneration; consequently, the disease persists beyond the onset of symptoms. There is a growing recognition of the need for treatments that could protect neurons and potentially modify the disease course because current PD treatments primarily address symptoms without halting the disease progression. Autophagy, a cellular process clearing damaged organelles and proteins, has emerged as a potential strategy for neuroprotection in PD. In this study, the object was to identify compounds with autophagy-inducing activity and neuroprotective effect, employing chemical library that reached Phase III trials or beyond (3,200 compounds). Among 547 CNS drugs, 25 exhibiting autophagy-inducing activity were selected and their concentration-dependent autophagy levels were examined. Furthermore, the neuroprotective effects were validated in a PD model induced in PC12 cells by treatment of 6-hydroxydopamine (6-OHDA). Consequently, Bicifadine, Sertraline, and Tiagabine were identified to possess autophagy-inducing activity and neuroprotective effects. These compounds demonstrated statistically significant results at concentrations of 0.3, 1, and 3 µM. This investigation proposes a novel alternative for PD treatment, considering the challenges in CNS drug development such as blood-brain barrier (BBB) penetration. The autophagy-inducing and neuroprotective effects hold the potential to slow or halt the progression of PD. Consequently, this study represents a significant step in the development of therapeutic methods for PD, underscoring the necessity for further understanding of the actual therapeutic efficacy and mechanisms of these compounds.