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

Abstract

3-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.