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

ABSTRACT: 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.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC9525707 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Zhu Zhou Z Liu Liang-Feng LF Su Cheng-Fu CF Liu Jia J Tong Benjamin Chun-Kit BC Iyaswamy Ashok A Krishnamoorthi Senthilkumar S Sreenivasmurthy Sravan Gopalkrishnashetty SG Guan Xin-Jie XJ Kan Yu-Xuan YX Xie Wen-Jian WJ Zhao Chen-Liang CL Cheung King-Ho KH Lu Jia-Hong JH Tan Jie-Qiong JQ Zhang Hong-Jie HJ Song Ju-Xian JX Li Min M

Acta pharmacologica Sinica 20220225 10

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 t ...[more]

PMID: 35217810

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Dataset Information

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

Publications

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

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