Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy
Zhou Zhu1,2,3,
Liang-feng Liu1,4,
Cheng-fu Su1,2,3,
Jia Liu1,2,3,
Benjamin Chun-Kit Tong1,2,3,
Ashok Iyaswamy1,2,3,
Senthilkumar Krishnamoorthi1,2,3,
Sravan Gopalkrishnashetty Sreenivasmurthy1,2,3,
Xin-jie Guan1,2,3,
Yu-xuan Kan1,2,3,
Wen-jian Xie2,
Chen-liang Zhao2,
King-ho Cheung1,2,3,
Jia-hong Lu5,
Jie-qiong Tan6,
Hong-jie Zhang2,
Ju-xian Song1,7,
Min Li1,2,3
1 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
2 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China
3 Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen 518057, China
4 Limin Pharmaceutical Factory, Livzon Group Limited, Shaoguan 512028, China
5 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China
6 Center for Medical Genetics and Hunan Key Laboratory of Animal Model for Human Diseases, School of Life Sciences, Central South University, Changsha 410078, China
7 Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
Correspondence to: Ju-xian Song: juxian.song@gmail.com, Min Li: limin@hkbu.edu.hk,
DOI: 10.1038/s41401-022-00871-0
Received: 12 July 2021
Accepted: 17 January 2022
Advance online: 25 February 2022
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.
