MPP+ LIKE N METHYLATED B CARBOLINES AND OXIDATIVE DAMAGE

描述（改编自申请人摘要）：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都是假设的。据推测，内源性MPP+类似物，如神经毒性n -甲基化β -碳碱（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5 -羟色胺能转运体主动积累到单胺能神经元中。其中，mebc +引起氧化应激，介导细胞功能障碍和死亡。系统：亲本lc - pk1细胞缺乏单胺转运体和lc - pk1细胞暴露于MeBC+， 2-甲基碘化和2,9- n， n -二甲基碘化。目的1：表征MeBC+诱导的细胞毒性与时间、MeBC+浓度和单个单胺转运蛋白表达的关系。目的2：在MeBC+暴露的亲本和表达转运蛋白的LLC-PK1培养物中比较氧化损伤的蛋白质、脂质和DNA。意义：PD中存在明显的氧化应激；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核也表现出病理。这些观察结果可能是由于PD中的活性物质；研究结果对通过减少MdBC+的摄取和随后的氧化损伤来减缓PD进展的治疗方法的发展至关重要。

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.