MPP+ LIKE N METHYLATED B CARBOLINES AND 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，但遗传和环境因素的作用是假设的。 据推测，内源性MPP+类似物，如神经毒性N-甲基化β-咔啉（MeBC+），可能有助于疾病的发病机制。 假设：MeBC+通过多巴胺、去甲肾上腺素和多巴胺能转运蛋白主动积累到单胺能神经元中。 其中，MeBC+引起氧化应激，其介导细胞功能障碍和死亡。 系统名称：缺乏单胺转运蛋白的亲本LLC-PK 1细胞和暴露于MeBC+、2-甲基碘化去甲哈尔曼铵和2，9-N，N-二甲基碘化去甲哈尔曼铵的LLC-PK 1细胞。 目的1：表征MeBC+诱导的细胞毒性作为时间、MeBC+浓度和单个单胺转运蛋白表达的函数。 目的2：在MeBC+暴露的亲本和表达转运蛋白的LLC-PK 1培养物中比较氧化损伤的蛋白质、脂质和DNA。 重要性：氧化应激在PD中是明显的;主要受影响的是多巴胺能系统，但去甲肾上腺素能和多巴胺能核也表现出病理学。 这些观察结果可能是由于PD中的活性药物;结果对于开发可以通过减少MdBC+摄取和随后的氧化损伤来减缓PD进展的疗法至关重要。

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.