MPP+ LIKE N METHYLATED B CARBOLINES AND OXIDATIVE DAMAGE

MPP 类似 N 甲基化 B 咔啉和氧化损伤

• 批准号: 6393254
• 负责人: DEBRA A GEARHART
• 金额: $ 4.2万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6393254
• 关键词: DNA damage; Parkinson's disease; cell line; disease /disorder model; dopamine transporter; lipid peroxides; mazindol; methylation; methylphenyltetrahydropyridine; neural degeneration; neurotoxins; oxidative stress; pyridoindole; serotonin transporter; transfection

DESCRIPTION (Adapted from applicant's abstract): The etiology of idiopathic Parkinson's disease (PD) has not been elucidated, but roles for both genetic and environmental factors are hypothesized. It is postulated that endogenous MPP+ -analogs, such as neurotoxic N-methylated beta-carbolines (MeBCs+), may contribute to disease pathogenesis. Hypothesis: MeBCs+ are actively accumulated into monoaminergic neurons via the dopamine, norepinephrine, and serotonergic transporters. Therein, MeBCs+ cause oxidative stress, which mediates cellular dysfunction and death. System: Parental LLC-PK1 cells that lack monoamine transporters and LLC-PK1 cells exposed to the MeBC+, 2-methylnorharmanium iodide and 2,9-N, N-dimethylnorharmaniusm iodide. Aim 1: Characterize MeBC+-induced cytotoxicity as a function of time, MeBC+ concentration and expression of individual monoamine transporters. Aim 2: Compareoxidatively-damaged proteins, lipids, and DNA in MeBC+-exposed parental and transporter-expressing LLC-PK1 cultures. Significance: Oxidative stress is evident in PD; primarily affected is the dopaminergic system, but noradrenergic and serotonergic nuclei also exhibit pathology. These observations may be due to active agents in PD; results are fundamental to the development of therapies that could slow the progression of PD by reducing MdBC+ uptake and consequent oxidative damage.

描述（改编自申请人的摘要）：特发性帕金森病（PD）的病因尚未阐明，但假设了遗传和环境因素的作用。 据推测，内源性 MPP+ 类似物，例如神经毒性 N-甲基化 β-咔啉 (MeBCs+)，可能有助于疾病发病机制。 假设：MeBCs+ 通过多巴胺、去甲肾上腺素和血清素转运蛋白主动积累到单胺能神经元中。 其中，MeBC+ 会引起氧化应激，从而介导细胞功能障碍和死亡。 系统：缺乏单胺转运蛋白的亲本 LLC-PK1 细胞和暴露于 MeBC+、2-甲基正碘化鎓和 2,9-N,N-二甲基正鲎碘化物的 LLC-PK1 细胞。 目标 1：表征 MeBC+ 诱导的细胞毒性随时间、MeBC+ 浓度和单个单胺转运蛋白表达的变化。 目标 2：比较暴露于 MeBC+ 的亲代培养物和表达转运蛋白的 LLC-PK1 培养物中氧化损伤的蛋白质、脂质和 DNA。 意义：氧化应激在帕金森病中很明显；主要受影响的是多巴胺能系统，但去甲肾上腺素能和血清素能细胞核也表现出病理学。 这些观察结果可能是由于帕金森病中的活性药物所致；这些结果对于开发可通过减少 MdBC+ 摄取和随之而来的氧化损伤来减缓 PD 进展的疗法至关重要。