PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease

描述（由申请人提供）：大多数帕金森病（PD）病例的病因不明（约90%是“散发性”），而约10%是由于纯粹的遗传因素。长期以来，人们一直怀疑是环境因素造成的，但没有发现令人信服的有毒物质。许多不同种类的化合物，包括杀虫剂和溶剂，都与帕金森病有关。这一提议验证了这样的假设：暴露于杂环胺，2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP），一种已知的啮齿动物致癌物，复制了人类帕金森病（PD）的关键特征。目前，关于慢性PhIP的神经学影响的初步数据很少。然而，有四个关键因素导致人们提出PhIP在pd相关神经退行性变中的作用。1)我们小组成员的初步研究显示pd相关的小鼠运动缺陷2)结构相关的杂环胺在大鼠中的多巴胺能效应3)人类高水平消费的潜力。PhIP是从熟肉皮中分离出来的最丰富的氨基咪唑氮杂芳烃（高达15ug/kg生肉）。4)PhIP和PhIP的代谢物穿过血脑屏障，因此可能对不同的神经元核有直接影响。本提案的主要目标是：1)确定大鼠慢性给药PhIP是否繁殖

DESCRIPTION (provided by applicant): The causes of most Parkinson's disease (PD) cases are unknown (~90% are "sporadic"), while ~10 % are due to purely inherited factors. Environmental factors have long been suspected, but no toxicant has been convincingly identified. Numerous diverse classes of compounds, including pesticides and solvents have been linked to PD. This proposal tests the hypothesis that: exposure to the heterocyclic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), a known carcinogen in rodents, replicates key features of human Parkinson's disease (PD). Currently, there are little preliminary data on the neurological effects of chronic PhIP. However, four key factors have led to proposing a role for PhIP in PD-relevant neurodegeneration. 1) A preliminary study from members of our group showing PD-relevant motor deficits in mice 2) Published dopaminergic effects of structurally related heterocylic amines in rats 3) Potential for high-level human consumption. PhIP is the most abundant amino-imidazoazaarene isolated from the crust of cooked meat (up to 15ug/kg uncooked meat) and 4) PhIP and PhIP metabolites cross the blood-brain barrier and, therefore, may have direct effects on distinct neuronal nuclei. The major goals of this proposal are to: 1) Determine if chronic administration of PhIP in the rat reproduces the key features of PD and 2) Identify potential mechanisms of toxicity using in vitro approaches. In this proposal, the following aims will be carried out: Aim 1. To determine if chronic PhIP administration replicates the key features of PD. Aim 2. To identify mechanisms of neurotoxicity of PhIP using a primary midbrain culture system. Success of this proposal would lead to at least three major advances in PD research. 1. Identification of a possible causative factor. PhIP is a common toxicant produced in meat preparation and may be consumed in single high doses and chronically vs. most rarely encountered dopaminergic toxicants. Success of this proposal would likely prompt epidemiological studies. Further, alterations in meat preparation are available, reducing PhIP formation and a potential PD-relevant exposure. 2. Development of a new PD model. There are numerous PD models, each with advantages/ disadvantages. None have adequately considered dietary factors. Current models have also failed to predict clinical trial successes and a novel model may prove to be more successful. 3. New PD mechanisms. If PhIP exposure reproduces the key PD features, mechanistic studies would be expected to identify novel pathogenic pathways that may be therapeutic targets. In summary, using both in vivo and in vitro systems we will carefully characterize neurodegeneration after PhIP exposure and preliminarily identify mechanisms of toxicity relevant to effects on the nigrostriatal dopamine system.