Repeated treatments with the D1 dopamine receptor agonist SKF-38393 modulate cell viability via sustained ERK-Bad-Bax activation in dopaminergic neuronal cells.

This study investigated the effects of SKF-38393 on dopaminergic neuronal cell death in a 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD) and PC12 cells. In the PD model, SKF-38393 administration (3 and 10 mg/kg per day, s.c.) for 8 weeks significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells in nigrostriatal regions. SKF-38393 administration for 8 weeks induced phosphorylation of sustained ERK1/2 and Bad (Bcl-2-associated death promoter) at Ser155 (BadSer155), and augmented Bax (Bcl-2-associated X protein) expression. However, SKF-38393 only increased Bad phosphorylation at Ser112 (BadSer112) when administered for 4 weeks. In PC12 cells, toxic levels of SKF-38393 (20 and 50 µM) rapidly induced formation of neurite-like processes, but not in the presence of an adenylyl cyclase inhibitor (MDL-12330 A). SKF-38393 (20 and 50 µM) induced sustained ERK1/2 and BadSer155 phosphorylation as well as caspase-3 activation. At a non-toxic level (5 µM), SKF-38393 produced only transient ERK1/2 and BadSer112 phosphorylation. Repeated treatments with SKF-38393 (5 µM) for 1-3 days activated BadSer112. Repeated treatments for 4-7 days induced sustained ERK1/2 and BadSer155 phosphorylation as well as Bax and caspase-3 activation. These results suggest that SKF-38393 induces neurotoxicity by activation of the sustained ERK-Bad-Bax system. These findings contribute to an understanding of the adverse effects of D1 dopamine receptor agonis...

Source: Behavioural Brain Research - March 27, 2019 Category: Neurology Authors: Park HJ, Zhao TT, Park KH, Lee MK Tags: Behav Brain Res Source Type: research