OXIDATION CHEMISTRY OF INDOLES

吲哚的氧化化学

基本信息

批准号：
3281131
负责人：
GLENN DRYHURST
金额：
$ 23.78万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
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/3281131
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

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

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项目摘要

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.

化学或生化过程导致变性阿尔茨海默氏病（AD）中大脑的选择性区域尚不清楚。它然而，众所周知，AD中存在严重的血清素能功能障碍。此外，吲哚前神经递质5-羟基丙胺（5-HT）和相关的中央吲哚很容易被氧化化合物。一些氧化当对小鼠中心施用时，产品引起了深刻的行为响应，并导致发射器耗竭和/或代谢物破坏在儿茶酚胺能，血清素能和胆碱能神经元系统中，即，在AD中受到最深远影响的系统。身份不明但被氧化脑脊液中存在5-HT和其他中央吲哚的形式 AD患者，但不在年龄匹配的对照中。和条件似乎存在于阿尔茨海默氏症脑组织中，应促进氧化反应。总之，这一证据导致了一个假设阿尔茨海默氏症大脑中血清素能系统的缺陷导致异常形成毒素的中央吲哚的氧化。该假设进一步提出这些毒素不仅攻击父母血清素能神经元，还攻击主要是raphe核，但被释放并在物理上攻击近端去甲肾上腺素基因座和胆碱能核底层核核复杂的。这三个结构起源于同条核心和投影到大脑的皮质区域，相当有选择地在AD中退化。该提案的具体目的是阐明氧化化学在实验条件下中央吲哚的生物化学可能与阿尔茨海默氏症脑组织中存在的患者有关。最终的产品将被筛选以进行毒性和行为反应遵循小鼠和大鼠的中央给药。主动的影响在儿茶酚胺能血清素能和胆碱能神经元上的药物系统将通过神经递质/代谢物分析研究。在为了更充分了解活性药物的作用方式，研究发射机摄取/释放过程的影响，对关键生物合成和计划生物降解酶和CNS受体。组织化学和微观研究将用于评估神经元损害或破坏。有毒的化学机制将研究某些活性药物的影响。证据也将试图证明中央吲哚会经历氧化反应即使在非病理衰老的条件下，可能是广告中大大加速。最终，预计这些研究可能会为神经元的某些方面提供重要的见解 AD基础的退化和生化缺陷。