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

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

  • Acta Pharmacol Sin. 2022 Oct;43(10):2511-2526. doi: 10.1038/s41401-022-00871-0.
Zhou Zhu 1 2 3,  Liang-Feng Liu 1 4,  Cheng-Fu Su 1 2 3,  Jia Liu 1 2 3,  Benjamin Chun-Kit Tong 1 2 3,  Ashok Iyaswamy 1 2 3,  Senthilkumar Krishnamoorthi 1 2 3,  Sravan Gopalkrishnashetty Sreenivasmurthy 1 2 3,  Xin-Jie Guan 1 2 3,  Yu-Xuan Kan 1 2 3,  Wen-Jian Xie 2,  Chen-Liang Zhao 2,  King-Ho Cheung 1 2 3,  Jia-Hong Lu 5,  Jie-Qiong Tan 6,  Hong-Jie Zhang 2,  Ju-Xian Song 7 8,  Min Li 9 10 11
Affiliations

Affiliations

  • 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 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. [email protected].
  • 8 Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. [email protected].
  • 9 Mr. & Mrs. Ko Chi-Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. [email protected].
  • 10 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, SAR, China. [email protected].
  • 11 Institute for Research and Continuing Education, Hong Kong Baptist University, Shenzhen, 518057, China. [email protected].
PMID: 35217810 DOI: 10.1038/s41401-022-00871-0
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.

Keywords

MPP+; PI3P; PIK3C3 complex; Parkinson’s disease; autophagy; corynoxine B; dopaminergic neuron; oxindole alkaloid.

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