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Article: Unexpected Neuronal Protection of SU5416 against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthase

TitleUnexpected Neuronal Protection of SU5416 against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthase
Authors
Issue Date2012
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2012, v. 7 n. 9, article no. e46253 How to Cite?
AbstractSU5416 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-tetrahydropyridine (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 IC 50 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. © 2012 Cui et al.
Persistent Identifierhttp://hdl.handle.net/10722/179467
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCui, Wen_US
dc.contributor.authorZhang, Zen_US
dc.contributor.authorLi, Wen_US
dc.contributor.authorMak, Sen_US
dc.contributor.authorHu, Sen_US
dc.contributor.authorZhang, Hen_US
dc.contributor.authorYuan, Sen_US
dc.contributor.authorRong, Jen_US
dc.contributor.authorChoi, TCen_US
dc.contributor.authorLee, SMYen_US
dc.contributor.authorHan, Yen_US
dc.date.accessioned2012-12-19T09:56:51Z-
dc.date.available2012-12-19T09:56:51Z-
dc.date.issued2012en_US
dc.identifier.citationPlos One, 2012, v. 7 n. 9, article no. e46253en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/10722/179467-
dc.description.abstractSU5416 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-tetrahydropyridine (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 IC 50 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. © 2012 Cui et al.en_US
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_US
dc.relation.ispartofPLoS ONEen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleUnexpected Neuronal Protection of SU5416 against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthaseen_US
dc.typeArticleen_US
dc.identifier.emailRong, J: jrong@hku.hken_US
dc.identifier.authorityRong, J=rp00515en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1371/journal.pone.0046253en_US
dc.identifier.pmid23049997-
dc.identifier.scopuseid_2-s2.0-84866666308en_US
dc.identifier.hkuros218905-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84866666308&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume7en_US
dc.identifier.issue9en_US
dc.identifier.spagearticle no. e46253-
dc.identifier.epagearticle no. e46253-
dc.identifier.isiWOS:000309556100168-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridCui, W=35191650200en_US
dc.identifier.scopusauthoridZhang, Z=24342569600en_US
dc.identifier.scopusauthoridLi, W=8853055600en_US
dc.identifier.scopusauthoridMak, S=35741097300en_US
dc.identifier.scopusauthoridHu, S=55328161100en_US
dc.identifier.scopusauthoridZhang, H=37762530600en_US
dc.identifier.scopusauthoridYuan, S=55344546300en_US
dc.identifier.scopusauthoridRong, J=7005980047en_US
dc.identifier.scopusauthoridChoi, TC=55366511700en_US
dc.identifier.scopusauthoridLee, SMY=35233892600en_US
dc.identifier.scopusauthoridHan, Y=8527680500en_US

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