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

Zhou Zhu, Liang-feng Liu, Cheng-fu Su, Jia Liu, Benjamin Chun Kit Tong, Ashok Iyaswamy, Senthilkumar Krishnamoorthi, Sravan Gopalkrishnashetty Sreenivasmurthy, Xin-jie Guan, Yu-xuan Kan, Wen-jian Xie, Chen-liang Zhao, King-ho Cheung, Jia-hong Lu, Jie-qiong Tan, Hong-jie Zhang, Ju-xian Song*, Min Li*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2511-2526
Number of pages16
JournalActa Pharmacologica Sinica
Volume43
Issue number10
Early online date25 Feb 2022
DOIs
Publication statusPublished - Oct 2022

Scopus Subject Areas

  • Pharmacology (medical)
  • Pharmacology

User-Defined Keywords

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

Fingerprint

Dive into the research topics of 'Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy'. Together they form a unique fingerprint.

Cite this