MPP+ LIKE N METHYLATED B CARBOLINES AND OXIDATIVE DAMAGE

描述(摘自申请者的摘要)：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-甲基化的β-Carolines(MeBCs+)，可能与疾病的发病有关。假设：MeBCs+通过多巴胺、去甲肾上腺素和5-羟色胺能转运体活跃地积聚到单胺能神经元中。其中，MeBCs+会引起氧化应激，从而导致细胞功能障碍和死亡。系统：缺乏单胺转运体的亲代LLC-PK1细胞和暴露于MeBC+，2-甲基去甲肾上腺素和2，9-N-二甲基去甲肾上腺素的LLC-PK1细胞。目的1：研究MeBC+诱导的细胞毒性与时间、浓度和单胺转运体表达的关系。目的：比较MeBC+暴露的亲本细胞和转运蛋白表达的LLC-PK1细胞中氧化损伤的蛋白质、脂质和DNA。意义：帕金森病患者存在明显的氧化应激；主要受累于多巴胺能系统，但去甲肾上腺素能和5-羟色胺能核团也表现出病理改变。这些观察结果可能是由于PD中的活性物质；结果是开发治疗方法的基础，这些治疗方法可以通过减少MDBC+摄取和随后的氧化损伤来减缓PD的进展。

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.