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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

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.

引起相当一部分生物退化的化学或生物化学过程阿尔茨海默氏病（AD）中大脑的选择性区域是未知的。它然而，已知AD中存在严重的肾上腺素能功能障碍。此外，吲哚神经递质5-羟色胺（5-HT）和相关的中心吲哚是容易氧化的化合物。一些氧化当集中给予小鼠时，反应，并导致递质消耗和/或代谢物破坏在儿茶酚胺能、胆碱能和胆碱能神经元系统中，也就是说，系统在AD中受到最深刻的影响。未鉴别但已氧化 5-羟色胺和其他中枢吲哚存在于脑脊液中而在年龄匹配的对照组中则没有。还有条件似乎存在于阿尔茨海默氏症的脑组织中，反应. 综合这些证据可以得出一个假设，阿尔茨海默氏症大脑中的多巴胺能系统的缺陷导致异常的中心吲哚氧化形成毒素。假设进一步提出这些毒素不仅攻击母体肾上腺素能神经元，主要是中缝核，但被释放和攻击身体近侧去甲肾上腺素能蓝斑和胆碱能基底核复杂. 这三种结构起源于等枝晶核心，投射到大脑皮层区域，在AD中退化。本提案的具体目的是阐明氧化化学和生物化学的中心吲哚在实验条件下，可能与阿尔茨海默病脑组织中存在的物质有关。将筛选所得产品的毒性和行为反应在小鼠和大鼠的中枢给药后。的具体应用方法及效果对儿茶酚胺能神经元、胆碱能神经元系统将通过神经递质/代谢物分析进行研究。在为了更全面地了解活性药物的作用模式，研究发射器的吸收/释放过程，对关键生物合成和生物降解酶和CNS受体。组织化学和微观研究将被用来评估特定区域的神经元损伤或破坏。有毒物质的化学机制将研究某些活性药物的作用。证据也将试图证明中心吲哚经历氧化反应即使在非病理性老化的条件下，在AD中大大加速。最终，这些研究预计可能会对神经元的某些方面提供重要的见解，变性和生化缺陷的潜在AD。