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

The D dopamine receptor agonist, SKF-38393, induces cytotoxicity in striatal dopaminergic neurons via an extracellular signal-regulated kinase (ERK) signaling cascade. However, the underlying mechanism remains unclear. We hypothesized that repeated activation of dopaminergic receptors by agonists could lead to neuronal cell death. 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 D dopamine receptor agonists in patients with PD.