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.
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Acknowledgements
We thank Roy Chun-laam Ng (The University of Hong Kong) and Karen Wong (The University of Hong Kong) for processing TEM samples; Zi-wan Ning (Hong Kong Baptist University) for performing pharmacokinetic analysis; Xiao-jian Shao (Hong Kong Baptist University) for analyzing LC-MS/MS data; and Dr. Martha Dahlen for the English editing. This study was supported by Hong Kong General Research Fund (GRF/HKBU12100618, GRF/HKBU12101417), the National Natural Science Foundation of China (81703487, 81773926), Shenzhen Science and Technology Innovation Commission (JCYJ20180507184656626, JCYJ20180302174028790), Hong Kong Health and Medical Research Fund (HMRF17182541, HMRF17182551, HMRF-17182561), and Research Fund from Hong Kong Baptist University (HKBU/RC-IRCs/17-18/03, IRCMS/19-20/H02, GDS-84/506/2019).
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JXS and ML designed the research; ZZ, LFL, CFS, JL, SGS, XJG, and YXK performed the main experiments; WJX and CLZ synthesized the compound CB6; ZZ, BCKT, AI, and SK analyzed the data; ZZ and JXS wrote the paper; ZZ, KHC, JHL, JQT, HJZ, JXS, and ML revised the paper; JXS and ML supervised the study.
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Zhu, Z., Liu, Lf., Su, Cf. et al. Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy. Acta Pharmacol Sin 43, 2511–2526 (2022). https://doi.org/10.1038/s41401-022-00871-0
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DOI: https://doi.org/10.1038/s41401-022-00871-0
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