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Article: Neuroprotective effects of atypical D 1 receptor agonist SKF83959 are mediated via D 1 receptor-dependent inhibition of glycogen synthase kinase-3β and a receptor-independent anti-oxidative action

TitleNeuroprotective effects of atypical D 1 receptor agonist SKF83959 are mediated via D 1 receptor-dependent inhibition of glycogen synthase kinase-3β and a receptor-independent anti-oxidative action
Authors
Issue Date2008
Citation
Journal Of Neurochemistry, 2008, v. 104 n. 4, p. 946-956 How to Cite?
Abstract3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3 - benzazepine (SKF83959), a selective agonist for the putative phosphatidylinositol (PI)-linked dopamine receptor (DAR), has been shown to possess potent anti-Parkinson disease effects but produces less dyskinesia and motor fluctuation that are frequently observed in Parkinson disease drug therapies. The present study was designed to detect the neuroprotection of SKF83959 and its potential mechanism for the effect in cultured rat cortical cells. The presence of SKF83959 with a dose range of 0.1-30 μmol/L improved H 2O 2-reduced cell viability in a dose-dependent manner. The anti-apoptotic action of SKF83959 was partially abolished by pre-application of the D 1 antagonist SCH23390 (30 μmol/L) and the PI 3-kinase (PI 3-K) inhibitor LY294002 but not by the MEK1/2 inhibitor PD98059 (30 μmol/L). Moreover, SKF83959 treatment significantly inhibited H 2O 2-activated glycogen synthase kinase-3β (GSK-3β) which was associated with the drug's neuroprotective effect, but this inhibition was attenuated by SCH23390 and a selective PI 3-K inhibitor. Moreover, the application of either SKF83959 or a pharmacological inhibitor of GSK-3β attenuated the inhibition by H 2O 2 on the expression of inducible NO synthase and production of NO. This indicates that D 1-like receptor, presumably PI-linked D 1 receptor, -mediated alteration of PI 3-K/Akt/GSK-3β pathway is involved in the neuroprotection by SKF83959. In addition, SKF83959 also effectively decreased the level of the lipid peroxidation and increased the activity of GSH-peroxidase altered by H 2O 2. These results suggest that SKF83959 exerts its neuroprotective effect through both receptor-dependent and independent mechanisms: Inhibition of GSK-3β and consequently increasing the expression of inducible NO synthase via putative PI-linked DAR; and its anti-oxidative activity which is independent of DAR. © 2007 The Authors.
Persistent Identifierhttp://hdl.handle.net/10722/179443
ISSN
2015 Impact Factor: 3.842
2015 SCImago Journal Rankings: 2.021
References

 

DC FieldValueLanguage
dc.contributor.authorYu, Yen_US
dc.contributor.authorWang, JRen_US
dc.contributor.authorSun, PHen_US
dc.contributor.authorGuo, Yen_US
dc.contributor.authorZhang, ZJen_US
dc.contributor.authorJin, GZen_US
dc.contributor.authorZhen, Xen_US
dc.date.accessioned2012-12-19T09:56:37Z-
dc.date.available2012-12-19T09:56:37Z-
dc.date.issued2008en_US
dc.identifier.citationJournal Of Neurochemistry, 2008, v. 104 n. 4, p. 946-956en_US
dc.identifier.issn0022-3042en_US
dc.identifier.urihttp://hdl.handle.net/10722/179443-
dc.description.abstract3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3 - benzazepine (SKF83959), a selective agonist for the putative phosphatidylinositol (PI)-linked dopamine receptor (DAR), has been shown to possess potent anti-Parkinson disease effects but produces less dyskinesia and motor fluctuation that are frequently observed in Parkinson disease drug therapies. The present study was designed to detect the neuroprotection of SKF83959 and its potential mechanism for the effect in cultured rat cortical cells. The presence of SKF83959 with a dose range of 0.1-30 μmol/L improved H 2O 2-reduced cell viability in a dose-dependent manner. The anti-apoptotic action of SKF83959 was partially abolished by pre-application of the D 1 antagonist SCH23390 (30 μmol/L) and the PI 3-kinase (PI 3-K) inhibitor LY294002 but not by the MEK1/2 inhibitor PD98059 (30 μmol/L). Moreover, SKF83959 treatment significantly inhibited H 2O 2-activated glycogen synthase kinase-3β (GSK-3β) which was associated with the drug's neuroprotective effect, but this inhibition was attenuated by SCH23390 and a selective PI 3-K inhibitor. Moreover, the application of either SKF83959 or a pharmacological inhibitor of GSK-3β attenuated the inhibition by H 2O 2 on the expression of inducible NO synthase and production of NO. This indicates that D 1-like receptor, presumably PI-linked D 1 receptor, -mediated alteration of PI 3-K/Akt/GSK-3β pathway is involved in the neuroprotection by SKF83959. In addition, SKF83959 also effectively decreased the level of the lipid peroxidation and increased the activity of GSH-peroxidase altered by H 2O 2. These results suggest that SKF83959 exerts its neuroprotective effect through both receptor-dependent and independent mechanisms: Inhibition of GSK-3β and consequently increasing the expression of inducible NO synthase via putative PI-linked DAR; and its anti-oxidative activity which is independent of DAR. © 2007 The Authors.en_US
dc.languageengen_US
dc.relation.ispartofJournal of Neurochemistryen_US
dc.subject.mesh2,3,4,5-Tetrahydro-7,8-Dihydroxy-1-Phenyl-1H-3-Benzazepine - Analogs & Derivatives - Pharmacologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntioxidants - Pharmacologyen_US
dc.subject.meshCell Survival - Drug Effects - Physiologyen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshCerebral Cortex - Drug Effects - Metabolismen_US
dc.subject.meshDopamine Agonists - Pharmacologyen_US
dc.subject.meshDose-Response Relationship, Drugen_US
dc.subject.meshGlycogen Synthase Kinase 3 - Antagonists & Inhibitors - Metabolismen_US
dc.subject.meshNeuroprotective Agents - Pharmacologyen_US
dc.subject.meshProtein Kinase Inhibitors - Pharmacologyen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshReceptors, Dopamine D1 - Agonistsen_US
dc.titleNeuroprotective effects of atypical D 1 receptor agonist SKF83959 are mediated via D 1 receptor-dependent inhibition of glycogen synthase kinase-3β and a receptor-independent anti-oxidative actionen_US
dc.typeArticleen_US
dc.identifier.emailZhang, ZJ: zhangzj@hkucc.hku.hken_US
dc.identifier.authorityZhang, ZJ=rp01297en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1111/j.1471-4159.2007.05062.xen_US
dc.identifier.pmid18005341-
dc.identifier.scopuseid_2-s2.0-38549147516en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-38549147516&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume104en_US
dc.identifier.issue4en_US
dc.identifier.spage946en_US
dc.identifier.epage956en_US
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridYu, Y=24829801200en_US
dc.identifier.scopusauthoridWang, JR=9942427500en_US
dc.identifier.scopusauthoridSun, PH=24765677100en_US
dc.identifier.scopusauthoridGuo, Y=43461300200en_US
dc.identifier.scopusauthoridZhang, ZJ=8061473900en_US
dc.identifier.scopusauthoridJin, GZ=7401563031en_US
dc.identifier.scopusauthoridZhen, X=16246797700en_US
dc.identifier.citeulike2313225-

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