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计划一种 在精神分裂症病因学中的重要作用。一直以来 假设儿茶酚胺神经元长期暴露于 过量的多巴胺或多巴胺的氧化代谢产物 可能导致神经元损伤和细胞死亡，并对此负有部分责任 治疗精神分裂症的一些消极症状。我们正在评估 用克隆儿茶酚胺能系统研究多巴胺的神经毒性作用 从小鼠中枢神经系统分离的细胞系(CATH.a细胞)。多巴胺 在CATH中产生时间和剂量依赖性的细胞死亡增加 细胞。细胞死亡也发生在用其他药物治疗后 儿茶酚胺，以及神经毒性化合物6-羟基多巴胺 和一氧化氮。细胞死亡不是受体介导的选择性死亡 去甲肾上腺素和多巴胺受体激动剂对CATH.a无影响 细胞存活率。多巴胺诱导细胞凋亡性死亡 凝胶电泳法和流式细胞术检测DNA片段化 分析。细胞凋亡似乎是由多巴胺自氧化产生的， 由于多巴胺治疗后细胞内过氧化产物增加，这 过氧化氢酶可抑制过氧化产物的增加和细胞死亡 和N-乙酰半胱氨酸。超氧化物歧化酶似乎在 近年来多巴胺氧化代谢产物的解毒作用 这种酶的抑制剂，氨基甲酸二乙酯，增强了多巴胺 诱导细胞死亡和由超氧化物生成器产生的细胞死亡， 富马酸二羟基酯。多巴胺还降低了许多激素的水平 帮助保护细胞免受自由基伤害的细胞成分， 包括超氧化物歧化酶、谷胱甘肽和抗氧化蛋白， BCL-2。此外，bc1-2反义寡核苷酸还增加了对肿瘤细胞的敏感性。 CATH.a细胞对多巴胺诱导细胞死亡。在试图定义 多巴胺诱导CATH.a细胞死亡的细胞途径 发现线粒体膜电位选择性降低 CATH.a细胞在加入多巴胺后的四小时内 媒体。这些发现表明，如果多巴胺的氧化产物 通过CATH.a细胞系的凋亡引起神经毒性，这 可能是通过对线粒体的选择性作用。

Overactive dopaminergic neurons in the brain are thought to plan 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 and cell death and be partially responsible for some of the negative symptoms of schizophrenia. We are evaluation the neurotoxic effects of dopamine by using a clonal catecholaminergic cell line isolated from the CNS of the mouse (CATH.a cells). Dopamine produces a time and dose dependent increase in cell death in CATH.a cells. Cell death also occurred after treatment with other catecholamines, as well as the neurotoxic compounds, 6-hydroxydopamine and nitric oxide. Cell death is not receptor mediated since selective noradrenergic and dopaminergic receptor agonists had no effect on CATH.a cell viability. Dopamine induces apoptotic cell death as indicated by DNA fragmentation measured by gel electrophoresis and by flow cytometric analysis. Apoptosis appears to be produced by dopamine autoxidation, since intracellular perodixes increase after dopamine treatment and this increase in peroxides and cell death can both be inhibited by catalase and n-acetylcysteine. Superoxide dismutase appears to be important in the detoxification of dopamine's oxidative metabolites since an inhibitor of this enzyme, diethycarbamate, potentiates both dopamine induced cell death and cell death produced by the superoxide generator, dihydroxyfumarate. Dopamine also decreased the levels of a number of cellular components that help protect cells from free radicals, including superoxide dismutase, glutathione and the antioxidant protein, bcl-2. In addition, antisense to bcl-2 increased the sensitivity of CATH.a cells to dopamine induced cell death. In an attempt to define the cellular pathway for dopamine-induced cell death in CATH.a cells, we found a selective decrease in the mitochondrial membrane potential in CATH.a cells within four hours after the addition of dopamine to the media. These findings indicate that the oxidative products if dopamine cause neurotoxicity through apoptosis in the CATH.a cell line and this may be through a selective action on mitochondria.