Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/5826
Title: Unexpected neuronal protection of SU5416 against 1- methyl-4-phenylpyridinium ion-induced toxicity via inhibiting neuronal nitric oxide synthase
Authors: Cui, W
Zhang, Z
Li, W
Mak, S
Hu, S
Zhang, H
Yuan, S
Rong, J
Choi, TC
Lee, SMY
Han, Y 
Keywords: Tyrosine kinase inhibitors
D-aspartate receptors
Parkinsons-disease
Phase-I
Expression
Cells
Bis(7)-Tacrine
Zebrafish
Growth
Neuroprotection
Issue Date: 25-Sep-2012
Publisher: Public Library of Science
Source: PLoS one, 25 Sept., 2012, v. 7, no. 9, e46253, p. 1-12 How to cite?
Journal: PLoS one 
Abstract: SU5416 was originally designed as a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) for cancer therapy. In this study, we have found for the first time that SU5416 unexpectedly prevented 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced neuronal apoptosis in cerebellar granule neurons, and decreased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri​dine(MPTP)-induced loss of dopaminergic neurons and impairment of swimming behavior in zebrafish in a concentration-dependent manner. However, VEGFR-2 kinase inhibitor II, another specific VEGFR-2 inhibitor, failed to reverse neurotoxicity at the concentration exhibiting anti-angiogenic activity, strongly suggesting that the neuroprotective effect of SU5416 is independent from its anti-angiogenic action. SU5416 potently reversed MPP⁺-increased intracellular nitric oxide level with an efficacy similar to 7-nitroindazole, a specific neuronal nitric oxide synthase (nNOS) inhibitor. Western blotting analysis showed that SU5416 reduced the elevation of nNOS protein expression induced by MPP⁺. Furthermore, SU5416 directly inhibited the enzyme activity of rat cerebellum nNOS with an IC50 value of 22.7 µM. In addition, knock-down of nNOS expression using short hairpin RNA (shRNA) abolished the neuroprotective effects of SU5416 against MPP⁺-induced neuronal loss. Our results strongly demonstrate that SU5416 might exert its unexpected neuroprotective effects by concurrently reducing nNOS protein expression and directly inhibiting nNOS enzyme activity. In view of the capability of SU5416 to cross the blood-brain barrier and the safety for human use, our findings further indicate that SU5416 might be a novel drug candidate for neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.
URI: http://hdl.handle.net/10397/5826
EISSN: 1932-6203
DOI: 10.1371/journal.pone.0046253
Rights: © 2012 Cui et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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