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

Autor: Zhu Z; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Liu LF; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Limin Pharmaceutical Factory, Livzon Group Limited, Shaoguan, 512028, China., Su CF; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Liu J; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Tong BC; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Iyaswamy A; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Krishnamoorthi S; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Sreenivasmurthy SG; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Guan XJ; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Kan YX; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Xie WJ; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China., Zhao CL; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China., Cheung KH; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China., Lu JH; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China., Tan JQ; Center for Medical Genetics and Hunan Key Laboratory of Animal Model for Human Diseases, School of Life Sciences, Central South University, Changsha, 410078, China., Zhang HJ; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China., Song JX; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. juxian.song@gmail.com.; Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. juxian.song@gmail.com., Li M; Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. limin@hkbu.edu.hk.; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. limin@hkbu.edu.hk.; Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China. limin@hkbu.edu.hk.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2022 Oct; Vol. 43 (10), pp. 2511-2526. Date of Electronic Publication: 2022 Feb 25.
DOI: 10.1038/s41401-022-00871-0
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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