OXIDATION CHEMISTRY OF INDOLES

阿尔茨海默病（AD）是一种神经退行性脑疾病， 超过450万的美国老年人深受其害。长期目标 这项竞争性的续约申请将继续调查 可能引发和传播神经退行性疾病的机制 发生在AD大脑中的过程。所有在AD中死亡的神经元 要么完全位于皮层和海马/杏仁核复合体中， 从不同的皮层下细胞体投射并连接到后者 大脑区域。神经元损伤的这种显著的解剖选择性 涉及许多神经递质系统表明， 神经退行性变的过程只有明确的起点和进展 沿着特定的连接神经通路。该项目旨在 探索AD是由于异常的 5-羟色胺（5-HT）和去甲肾上腺素（NE）的氧化反应 在长的肾上腺素能和去甲肾上腺素能神经元的轴突末梢中， 分别在它们支配毛细血管的点上， 皮质和海马体。红细胞从这些微血管中渗漏， 已知在AD中是异常可渗透的，提出提供局部的 与H2 O2反应的低分子量铁源，和/或 分子氧以产生引发氧化的氧自由基 5-HT和NE产生许多毒素异常代谢产物。这些毒素 被提议通过各种机制来加强它们自身的合成， 产生升高的神经元内O2-通量，H2 O2和HO。并唤起 肾上腺素能和去甲肾上腺素能神经元的退行性变性。 将提供证据表明，5-HT和NE摄取 机制可能发挥关键作用，在加强合成有毒的 代谢物，以便它们在轴突处以最高浓度形成 终末沿着肾上腺素能和去甲肾上腺素能纤维的长度。因此，在本发明中， 这些轴突终末可以作为毒素的点源， 母体肾上腺素能和去甲肾上腺素能神经元变性， 连接多巴胺能，胆碱能，多巴胺能和其他神经元， 机制包括：（a）与各种钙通道的相互作用 导致神经元内Ca 2+稳态破坏的受体;（B） 谷氨酸释放增加，产生NMDA受体介导的 （c）线粒体氧化磷酸化解偶联; 和（d）神经元内氧化还原循环反应， 氧自由基形成。 建议设立这种机制， AD脑中发生的解剖学选择性神经变性。 具体目标是：（a）阐明体外氧自由基介导的 5-HT和NE的氧化化学，并确定关键中间体， 这些反应的产物，即，推定的异常氧化代谢物 （PAOM）;和（2）采用体外和体内神经药理学/ 神经毒理学方法来鉴定PAOM， 神经退行性/神经生物学活动可能导致 AD中的神经元损伤。

Alzheimer's Disease (AD) is a neurodegenerative brain disorder that afflicts more than 4.5 million elderly Americans. The long-term objective of this competitive renewal application continues to be to investigate mechanisms that might initiate and propagate the neurodegenerative processes that occur in the AD brain. All neurons that die in AD are either located entirely in the cortex and hippocampus/amygdala complex or project from various subcortical cell bodies and connect to the latter brain regions. This remarkable anatomic selectivity of neuronal damage involving many neurotransmitter systems suggests that the neurodegenerative processes have defined starting points and progress only along specific connected neuronal pathways. This project is aimed at exploring the hypothesis that AD is initiated as a result of aberrant oxidation reactions of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in the axon terminals of long serotonergic and noradrenergic neurons, respectively, at the points where they innervate blood capillaries in the cortex and hippocampus. Leakage of erythrocytes from these microvessels, known to be abnormally permeable in AD, is proposed to provide a localized source of low molecular weight iron which reacts with H2O2 and/or molecular oxygen to generate oxygen radicals that initiate the oxidation of 5-HT and NE giving a number of toxin aberrant metabolites. These toxins are proposed to potentiate their own synthesis by various mechanisms that generate elevated intraneuronal fluxes of O2-., H2O2 and HO. and evoke a retrograde degeneration of serotonergic and noradrenergic neurons. Evidence will be provided to suggest that the 5-HT and NE uptake mechanisms might play key roles in potentiating synthesis of toxic metabolites so that they are formed at highest concentrations at axon terminals along the length of serotonergic and noradrenergic fibers. Thus, these axon terminals may serve as point sources of toxins that evoke the degeneration of parent serotonergic and noradrenergic neurons and connected glutamatergic, cholinergic, dopaminergic and other neurons by mechanisms that include: (a) interactions with various calcium channel receptors leading to disruption of intraneuronal Ca2+ homeostasis; (b) elevated release of glutamate with resultant NMDA receptor-mediated excitotoxicity; (c) uncoupling of mitochondrial oxidative phosphorylation; and, (d) intraneuronal redox cycling reactions with resultant cytotoxic oxygen radical formation. Such mechanisms are proposed to account for the anatomically-selective neurodegeneration that occurs in the AD brain. Specific aims are: (a) to elucidate the in vitro oxygen radical-mediated oxidation chemistry of 5-HT and NE and to identify key intermediates and products of these reactions, i.e., putative aberrant oxidative metabolites (PAOMs); and, (2) to employ in vitro and in vivo neuropharmacological/ neurotoxicological methods to identify PAOMs that possess neurodegenerative/ neurobiological activities that might contribute to neuronal damage in AD.