http://dx.doi.org/10.1111/bph.12004">
 

Document Type

Journal Article

Authors

Wei Cui, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Zaijun Zhang, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau
Wenming Li, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Shengquan Hu, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Shinghung Mak, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Huan Zhang, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Renwen Han, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Shuai Yuan, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau
Sai Li, Guangdong Province Key Laboratory of Pharmacodynamic, College of Pharmacy, Jinan University
Fei Sa, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau
Daping Xu, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau
Zhixiu Lin, School of Chinese Medicine, Chinese University of Hong Kong
Zhong Zuo, School of Pharmacy, Chinese University of Hong Kong
Jianhui Rong, School of Chinese Medicine, University of Hong Kong
Edmond Dik-Lung Ma, Department of Chemistry, Hong Kong Baptist University
Tony Chunglit Choi, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University
Simon My Lee, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau
Yifan Han, Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, Hong Kong Polytechnic University

Department/Unit

Department of Chemistry

Title

The anti-cancer agent SU4312 unexpectedly protects against MPP+-induced neurotoxicity via selective and direct inhibition of neuronal NOS

Language

English

Abstract

Background and Purpose SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity and further explored the underlying mechanisms. Experimental Approach MPP +-treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. Key Results SU4312 unexpectedly prevented MPP+-induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. Conclusions and Implication SU4312 exhibited neuroprotection against MPP+ at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Keywords

angiogenesis, MPP+, neuronal NOS, neuroprotection, Parkinson's disease, SU4312

Publication Date

2013

Source Publication Title

British Journal of Pharmacology

Volume

168

Issue

5

Start Page

1201

End Page

1214

Publisher

Wiley

ISSN (print)

00071188

ISSN (electronic)

14765381

This document is currently not available here.

Share

COinS