OXIDATION CHEMISTRY OF INDOLES

吲哚的氧化化学

• 批准号: 2176541
• 负责人: GLENN DRYHURST
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-09-15 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2176541
• 关键词: 5 hydroxytryptophan; Alzheimer's disease; autooxidation; brain mapping; brain metabolism; catecholamine inhibitor; cell components; disease /disorder model; dorsal raphe nucleus; drug screening /evaluation; electrical potential; electrochemistry; high performance liquid chromatography; histochemistry /cytochemistry; hydroxyindoleacetate; hydroxyl group; immunocytochemistry; indoles; infrared spectrometry; laboratory mouse; laboratory rat; locus coeruleus; mass spectrometry; neural degeneration; neurotoxins; neurotransmitter metabolism; neurotransmitter receptor; nuclear magnetic resonance spectroscopy; oxidation; peroxidases; receptor binding; serotonin; serotonin inhibitor; serotonin receptor; toxicant screening; tryptophan analog

The chemical or biochemical processes which cause degeneration of rather selective areas of the brain in Alzheimer's Disease (AD) are unknown. It is known, however, that there is a serious serotonergic dysfunction in AD. Furthermore, the indolic neurotransmitter 5-hydroxytryptamine (5-HT) and related central indoles are easily oxidized compounds. Some oxidation products when centrally administered to mice evoke profound behavioral responses, and cause transmitter depletions and/or metabolite disruptions in the catecholaminergic, serotonergic and cholinergic neuronal systems, i.e., systems most profoundly affected in AD. Unidentified but oxidized forms of 5-HT and other central indoles are present in cerebrospinal fluid of AD patients but not in that of age-matched controls. And, conditions appear to exist in Alzheimer brain tissue which should facilitate oxidation reactions. Taken together this evidence leads to a hypothesis that a defect in the serotonergic system in Alzheimer brain results in aberrant oxidations of central indoles forming toxins. The hypothesis further proposes that these toxins attack not only the parent serotonergic neurons, principally the raphe nuclei, but are released and attack the physically proximate noradrenergic locus coeruleus and the cholinergic nucleus basalis complex. These three structures originate in the isodendritic core and project to cortical regions of the brain and are rather selectively degenerated in AD. The specific aims of this proposal are to elucidate the oxidation chemistry and biochemistry of the central indoles under experimental conditions which might be relevant to those which exist in alzheimer brain tissue. Resulting products will be screened for toxicity and behavioral response following central administration to mice and rats. The effects of active drugs on the catecholaminergic serotonergic, and cholinergic neuronal systems will be investigated by neurotransmitter/metabolite analyses. In order to more fully understand the mode of action of active drugs, studies of transmitter uptake/release processes, effects on key biosynthetic and biodegradative enzymes, and on CNS receptors are planned. Histochemical and microscopic studies will be employed to assess specific regions of neuronal damage or destruction. Chemical mechanisms underlying the toxic effects of certain active drugs will be investigated. Evidence will also be sought to demonstrate that central indoles undergo oxidation reactions even under conditions of non-pathological aging, reactions which may be greatly accelerated in AD. Ultimately, it is expected that these studies might provide important insights into some aspects of the neuronal degeneration and biochemical defects underlying AD.

生物化学，生物化学引起的化学或生化过程 阿尔茨海默病(AD)的大脑选择性区域尚不清楚。它 然而，已知在AD中存在严重的5-羟色胺能功能障碍。 此外，吲哚类神经递质5-羟色胺(5-HT)和 相关的中心吲哚是容易被氧化的化合物。一些氧化作用 当产品集中在小鼠身上时，会引起深刻的行为学 反应，并导致递质耗竭和/或代谢物中断 在儿茶酚胺能、5-羟色胺能和胆碱能神经元系统中， 即在AD中受影响最深的系统。身份不明，但已被氧化 脑脊液中存在多种形式的5-羟色胺和其他中枢吲哚 而在年龄匹配的对照组中则不是。和，条件 似乎存在于阿尔茨海默病脑组织中，这应该会促进氧化 反应。综上所述，这些证据导致了一种假设 阿尔茨海默病患者脑内5-羟色胺能系统缺陷导致异常 中心吲哚的氧化形成毒素。该假说进一步 提出这些毒素不仅攻击亲代的5-羟色胺能神经元， 主要是中缝核团，但被释放并攻击身体 去甲肾上腺素能蓝斑和胆碱能基底核 很复杂。这三种结构起源于等树枝状核， 投射到大脑的皮质区域，而且相当有选择性 在公元后退化。 这项提议的具体目的是阐明氧化化学。 以及在实验条件下的中心吲哚的生物化学 可能与阿尔茨海默病脑组织中存在的那些相关。 产生的产品将进行毒性和行为反应筛查 在小鼠和大鼠集中给药后。主动性的影响 儿茶酚胺能、5-羟色胺能和胆碱能神经元的药物 系统将通过神经递质/代谢物分析进行研究。在……里面 为了更全面地了解活性药物的作用方式，研究 递质摄取/释放过程，对关键生物合成和 生物降解酶和中枢神经系统受体是计划的。组织化学 并将利用微观研究来评估特定的区域 神经元损伤或破坏。毒物背后的化学机制 某些活性药物的效果将被调查。证据也会 试图证明中心吲哚发生氧化反应 即使在非病理性老化的条件下，反应也可能是 在公元后大大加速。最终，预计这些研究将 可能会对神经元的某些方面提供重要的见解 变性和生化缺陷是阿尔茨海默病的基础。