TY - JOUR
T1 - Corynoxine B derivative CB6 prevents Parkinsonian toxicity in mice by inducing PIK3C3 complex-dependent autophagy
AU - Zhu, Zhou
AU - Liu, Liang-feng
AU - Su, Cheng-fu
AU - Liu, Jia
AU - Tong, Benjamin Chun Kit
AU - Iyaswamy, Ashok
AU - Krishnamoorthi, Senthilkumar
AU - Sreenivasmurthy, Sravan Gopalkrishnashetty
AU - Guan, Xin-jie
AU - Kan, Yu-xuan
AU - Xie, Wen-jian
AU - Zhao, Chen-liang
AU - Cheung, King-ho
AU - Lu, Jia-hong
AU - Tan, Jie-qiong
AU - Zhang, Hong-jie
AU - Song, Ju-xian
AU - Li, Min
N1 - Funding Information:
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).
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - autophagy
KW - corynoxine B
KW - dopaminergic neuron
KW - oxindole alkaloid
KW - Parkinson’s disease
KW - PI3P
KW - PIK3C3 complex
KW - MPP+
UR - http://www.scopus.com/inward/record.url?scp=85125179861&partnerID=8YFLogxK
UR - https://europepmc.org/articles/PMC9525707
U2 - 10.1038/s41401-022-00871-0
DO - 10.1038/s41401-022-00871-0
M3 - Journal article
C2 - 35217810
AN - SCOPUS:85125179861
SN - 1671-4083
VL - 43
SP - 2511
EP - 2526
JO - Acta Pharmacologica Sinica
JF - Acta Pharmacologica Sinica
IS - 10
ER -