DOPAMINE-INDUCED NEUROTOXICITY IN A CATECHOLAMINERGIC CELL LINE

大脑中过度活跃的多巴胺能神经元被认为起到了作用

Overactive dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. It has been hypothesized that prolonged exposure of catecholamine neurons to excessive levels of dopamine or the oxidative metabolites of dopamine may produce neuronal damage, cell death, and be partially responsible for some of the negative symptoms of schizophrenia. Catecholamines have been shown to be neurotoxic to norepinephrine and dopamine neurons in primary culture (J Neurosci Res 26:428, 1990; J Pharmacol Exp Ther 262:1274, 1992). We are evaluating the neurotoxic effects of dopamine by using a clonal cell line developed by Chikaraishi and co-workers (J Neurosci 13:1280, 1993). This cell line was derived from a tyrosine hydroxylase positive tumor obtained from the CNS of transgenic mice carrying the SV 40 T antigen oncogene under the transcriptional control of the rat tyrosine hydroxylase gene. We found that incubation of CATH.a cells with dopamine produced dose-dependent cell death, with the highest concentration of dopamine (500 mM) killing 80% of the cells relative to untreated cells. This cell death was found to be due to apoptosis as evaluated by DNA fragmentation using gel-electrophoresis techniques and flow cytometry analysis. Apoptosis appeared to be produced by dopamine autoxidation, since intracellular peroxides increase after dopamine treatment, and cell death was inhibited by catalase. Bcl-2 levels decrease in a dose dependent manner in response to dopamine. These findings suggest that the oxidative products of dopamine cause neurotoxicity and can regulate bcl-2 levels. The regulation of bcl-2 may be important in deterring the neurodegeneration of dopamine neurons in Parkinson's disease.