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The anti-cancer agent SU4312 unexpectedly protects against MPP+- induced neurotoxicity via selective and direct inhibition of neuronal NOS
Cui W.1; Zhang Z.2,3; Li W.1,4; Hu S.1; Mak S.1; Zhang H.1; Han R.1; Yuan S.2; Li S.5; Sa F.2; Xu D.2; Lin Z.6; Zuo Z.7; Rong J.6; Ma E.D.-L.8; Choi T.C.1; Lee S.M.2; Han Y.1
2013
Source PublicationBritish Journal of Pharmacology
ISSN71188
Volume168Issue:5Pages:1201
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.

KeywordAngiogenesis Mpp++++ Neuronal Nos Neuroprotection Parkinson's Disease Su4312
DOI10.1111/bph.12004
URLView the original
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000315299700014
The Source to ArticleScopus
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Cited Times [WOS]:39   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorLee S.M.; Han Y.
Affiliation1.Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, , Hong Kong, China
2.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, , Macau, China
3.Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, , Guang Zhou, China
4.Departments of Pharmacology and Neurology, Emory University School of Medicine, , Atlanta, GA, 30322 USA
5.Institute of New Drug Research, Guangdong Province Key Laboratory of Pharmacodynamic, Constituents of Traditional Chinese Medicine & New Drug Research, College of Pharmacy, Jinan University, , Guang Zhou, China
6.School of Chinese Medicine, The Chinese University of Hong Kong, , Hong Kong, China
7.School of Pharmacy, The Chinese University of Hong Kong, , Hong Kong, China
8.Department of Chemistry, Hong Kong Baptist University, , Hong Kong, China
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Cui W.,Zhang Z.,Li W.,et al. The anti-cancer agent SU4312 unexpectedly protects against MPP+- induced neurotoxicity via selective and direct inhibition of neuronal NOS[J]. British Journal of Pharmacology,2013,168(5):1201.
APA Cui W..,Zhang Z..,Li W..,Hu S..,Mak S..,...&Han Y..(2013).The anti-cancer agent SU4312 unexpectedly protects against MPP+- induced neurotoxicity via selective and direct inhibition of neuronal NOS.British Journal of Pharmacology,168(5),1201.
MLA Cui W.,et al."The anti-cancer agent SU4312 unexpectedly protects against MPP+- induced neurotoxicity via selective and direct inhibition of neuronal NOS".British Journal of Pharmacology 168.5(2013):1201.
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