DOPAMINE-INDUCED NEUROTOXICITY IN A CATECHOLAMINERGIC CELL LINE

儿茶酚胺能细胞系中多巴胺诱导的神经毒性

• 批准号: 3781515
• 负责人: J M MASSERANO
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3781515
• 关键词: antiparkinson drugs; catecholamines; clone cells; cytotoxicity; dopamine; dopamine agonists; dopamine antagonists; dopamine receptor; neuropharmacology; neurotoxins

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 to 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 muM) killing 65% of the cells relative to untreated cells. We evaluated the possibility that the toxicity of dopamine is a receptor-mediated phenomenon by using a variety of D1 and D2 agonists and antagonists. Quinpirole, a selective D2 agonist was not neurotoxic, whereas incubation of CATH.a cells with D1 agonists (6-Bromo APA, SKF 38393) produced a dose-dependent cell death, with 84% of the cells dying at a concentration of 100 muM. Incubation of the cells with 10 muM of the selective D1 antagonists (SCH 23390, SKF 83566) produced no cell death. The concomitant treatment of the cells with D1 agonists (100 muM) and D1 antagonists (100 muM) partially prevented the neurotoxicity of the D1 agonists. These data support the hypothesis that dopamine is neurotoxic to catecholaminergic neurons and that this neurotoxicity is partially mediated by D1 receptors.

大脑中过度活跃的多巴胺能神经元被认为扮演着一种 在精神分裂症病因学中的重要作用。它是被假设的 使儿茶酚胺神经元长期暴露在过量的 多巴胺或多巴胺的氧化代谢产物可产生神经元 损害，细胞死亡，并对一些负面因素负有部分责任 精神分裂症的症状。儿茶酚胺已被证明具有神经毒性 去甲肾上腺素和多巴胺神经元的原代培养(J Neurosci Res) 26：428,1990；《药学实验杂志》262：1274,1992)。我们正在评估 用克隆细胞系研究多巴胺的神经毒性 Chikaraishi和同事(J Neurosci 13：1280,1993)。这株细胞系 来源于一个酪氨酸羟基酶阳性的肿瘤，取自 携带SV 40T抗原癌基因的转基因小鼠 大鼠酪氨酸羟化酶基因的转录调控。我们发现 CATH.a细胞与多巴胺孵育产生剂量依赖性细胞 死亡，最高浓度的多巴胺(500微米)杀死65% 这些细胞相对于未经处理的细胞。我们评估了一种可能性 多巴胺的毒性是一种受体介导的现象，通过使用一种 D_1和D_2激动剂和拮抗剂的种类。昆匹罗，一种选择性的D2 激动剂没有神经毒性，而CATH.a细胞与D_1孵育 激动剂(6-溴-APA，SKF 38393)可引起剂量依赖性的细胞死亡， 在100微米的浓度下，84%的细胞死亡。孵化 细胞中含有10微米的选择性D1拮抗剂(SCH 23390，SKF 83566)没有细胞死亡。伴随着细胞的治疗 D_1激动剂(100微米)和D_1拮抗剂(100微米)可部分阻断 D1激动剂的神经毒性。这些数据支持这样的假设 多巴胺对儿茶酚胺能神经元有神经毒性，这 神经毒性部分由D1受体介导。