Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy

Increasing evidence shows that Autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal Autophagy Inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent Autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 μM) dose-dependently accelerated Autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP⁺-treated PC12 cells, CB6 inhibited cell Apoptosis and increased cell viability by inducing Autophagy. In MPTP-induced mouse model of PD, oral administration of CB6 (10, 20 mg· kg^-1_· d^-1, for 21 days) significantly improved motor dysfunction and prevented the loss of dopaminergic neurons in the striatum and substantia nigra pars compacta. Collectively, compound CB6 is a brain-permeable Autophagy enhancer via PIK3C3 complex activation, which may help the prevention or treatment of PD.