Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson's disease

Although the toxin g-hydroxydopamine (6-OHDA) is utilized extensively in an imal models of Parkinson's disease, the underlying mechanism of its toxic e ffects on dopaminergic neurons is not completely understood. We examined th e effects of 6-OHDA on the CNS-derived tyrosine hydroxylase expressing B65 cell line, with particular attention to the regulation of the extracellular signal-regulated protein kinases (ERK), 6-OHDA elicited a dose-dependent c ytotoxicity in B65 cells. Toxic doses of 6-OHDA also elicited a biphasic pa ttern of ERK phosphorylation with a prominent sustained phase, a pattern th at differed from that observed with hydrogen peroxide (H2O2) treatment, 6-O HDA-elicited ERK phosphorylation was blocked by PD98059, an inhibitor of th e upstream mitogen activated protein kinase kinase (MEK) that phosphorylate s and activates ERK. PD98059 also conferred protection against 6-OHDA cytot oxicity, but did not affect H2O2 toxicity in B65 cells. These results sugge st that ERK activation plays a direct mechanistic role in 6-OHDA toxicity, rather than representing a protective compensatory response, and raise the possibility that abnormal patterns of ERK activation may contribute to dopa minergic neuronal cell death.