Reactive gamma-Ketoaldehydes in Dementia

痴呆症中的反应性γ-酮醛

• 批准号: 7369680
• 负责人: L Jackson Roberts, II
• 金额: $ 26.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369680
• 关键词: Acetylcholine; Acyltransferase; Age; Age-Months; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Antibodies; Antioxidants; Apolipoprotein E; Apoptosis; Arachidonic Acids; Behavioral; Brain; Calpain; Cell Death; Cessation of life; Data; Dementia; Development; Diet; Disease; Docosahexaenoic Acids; Endopeptidases; Exhibits; Folate; Free Radicals; Goals; Growth Factor Receptors; Hippocampus (Brain); Homocysteine; Homocystine; Human; Hyperhomocysteinemia; Immunoprecipitation; In Vitro; Injury; Insulinase; Intercept; Intervention; Isoprostanes; Knockout Mice; Memory; Memory impairment; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Performance; Play; Prostaglandins; Proteasome Inhibition; Protein Overexpression; Proteins; Pyridoxamine; Risk Factors; Role; Supplementation; Testing; Thioctic Acid; Time; Transgenic Organisms; Tubulin; adduct; age related; aged; aging brain; apolipoprotein E-4; cognitive function; crosslink; feeding; immunoreactivity; improved; ketoaldehyde; link protein; mouse model; multicatalytic endopeptidase complex; nervous system disorder; neuron loss; neuronal growth; novel; oxidation; peroxidation; prevent; protein aggregate; protein aggregation; protein crosslink; tau Proteins; tempol

DESCRIPTION (provided by applicant): Many established risk factors for dementia induce oxidative injury including age, amyloid Beta, hyperhomocysteinemia, and ApoE4. We have established the occurrence of oxidant injury in neurodegenerative diseases, in particular Alzheimer's disease (AD), by demonstrating overproduction of isoprostanes (IsoPs), neuroprostanes (NPs) products of free radical induced oxidation of arachidonic acid and docosahexaenoic acid, respectively. Isoketals (IsoKs) and neuroketals (NKs) are highly reactive gamma-ketoaldehydes produced by the IsoP and NP pathways, respectively. IsoKs and NKs rapidly adduct to proteins and exhibit a unique proclivity to cross link proteins. Recently, we found that pyridoxamine effectively traps and prevents IsoKs from adducting to proteins in vitro. A dominant feature of Alzheimer's disease is the accumulation of aggregated proteins. Proteasome activity is also impaired in Alzheimer's disease, which can induce apoptosis. The cause of protein aggregation, proteasome inhibition, and the relationship between these phenomena is poorly understood. Recently, we found intense IsoK immunoreactivity in hippocampal neurons in AD brains, which was absent in brains from aged-matched controls. IsoK adducted proteins are poorly degraded by the 20S proteasome and also inhibit proteasome function, lsoKs inhibit proteasome function and induce cell death at nM concentrations in neuroglial cells. These findings have engendered the hypothesis that oxidative injury in Alzheimer's disease and likely other forms of dementia produces IsoKs and NKs, which adduct to proteins and alter neuronal function, inhibit proteasome function, and induce neuronal cell death. To test this hypothesis, we will determine the levels and distribution of IsoK/NK adducts in post-mortem brains from patients with Alzheimer's disease and determine whether IsoK/NK adducts are present in CSF from AD patients. We recently established the occurrence of oxidant injury in an animal model of dementia that is associated with severe memory deficit, aged ApoE null mice overexpressing human ApoE4. We will determine the time-course of development and progression of memory deficit; increased formation of IsoPs, NPs, IsoK/NK adducts, and changes in protease activity in these animals. We will identify IsoK/NK adducted proteins in the hippocampus of AD brains and in brains of the mouse model of dementia. We will also determine the efficacy of 2 antioxidants, Tempol and lipoic acid, to suppress oxidative stress, IsoK/NK adduct formation, and mitigate the memory deficit in the mouse model. We will also explore a novel pharmacologic intervention, the ability of pyridoxamine to selectively prevent IsoK/NK adduction and mitigate the memory deficit in the mouse model.

描述（由申请人提供）：许多已建立的痴呆症危险因素诱导氧化损伤，包括年龄，淀粉样蛋白β，高脑结构血症和APOE4。我们已经通过证明异丙烷（ISOPS）的过量生产，神经前列腺（NPS）产物的自由基诱导的蛛网膜酸和docosahexahexaenoic acid的产物，确定了神经退行性疾病（尤其是阿尔茨海默氏病（AD））中氧化剂损伤的发生。 Isoketals（ISOKS）和神经摄氏（NKS）分别是由ISOP和NP途径产生的高反应性γ-酮醛。 ISOK和NKS迅速加入蛋白质，并表现出对交叉链接蛋白的独特倾向。最近，我们发现吡id胺有效地捕获并阻止ISOK在体外加入到蛋白质上。阿尔茨海默氏病的主要特征是聚集蛋白的积累。蛋白酶体的活性在阿尔茨海默氏病中也受到损害，这可能诱导凋亡。蛋白质聚集，蛋白酶体抑制以及这些现象之间的关系的原因很少。最近，我们发现AD大脑中海马神经元中的ISOK免疫反应性强烈，这在老年匹配的对照中没有大脑中。 ISOK加合蛋白因20S蛋白酶体而降解不良，并抑制蛋白酶体功能，LSOKS抑制蛋白酶体功能，并诱导神经胶质细胞中NM浓度的细胞死亡。这些发现提出了这样一个假设，即阿尔茨海默氏病中的氧化损伤以及其他形式的痴呆症可能产生ISOK和NKS，它们会加入蛋白质并改变神经元功能，抑制蛋白酶体功能，并诱导神经元细胞死亡。为了检验这一假设，我们将确定来自阿尔茨海默氏病后验尸大脑中ISOK/NK加合物的水平和分布，并确定AD患者的CSF中是否存在ISOK/NK加合物。我们最近确定了与严重的记忆缺陷，衰老的apoe null小鼠过表达人APOE4有关的痴呆模型中氧化剂损伤的发生。我们将确定记忆不足的发展和发展的时间顺序；这些动物中ISOP，NP，ISOK/NK加合物的形成增加以及蛋白酶活性的变化。我们将在广告大脑的海马和痴呆症小鼠模型的大脑中鉴定ISOK/NK加合蛋白。我们还将确定抑制氧化应激，ISOK/NK加合物形成并减轻小鼠模型中的记忆缺陷的2种抗氧化剂和lipoic酸的疗效。我们还将探索一种新型的药理干预措施，吡id胺选择性预防ISOK/NK内收并减轻小鼠模型中的记忆不足的能力。

项目成果

Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent γ-Ketoaldehyde Scavenger, by LC/MS/MS.

通过 LC/MS/MS 测定水杨胺（一种有效的 γ-酮醛清除剂）的药代动力学和口服生物利用度。

• DOI: 10.3390/pharmaceutics2010018
• 发表时间: 2010
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Zagol-Ikapitte,IreneA;Matafonova,Elena;Amarnath,Venkataraman;Bodine,ChristopherL;Boutaud,Olivier;Tirona,RommelG;Oates,JohnA;Roberts2nd,LJackson;Davies,SeanS
• 通讯作者: Davies,SeanS