2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans

2-羟基苄胺预防阿尔茨海默病：对人类的初步评估

• 批准号: 9564351
• 负责人: John A Rathmacher
• 金额: $ 15.06万
• 依托单位: METABOLIC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564351
• 关键词: Address; Adult; Adverse effects; Adverse event; Affect; Age-associated memory impairment; Aging; Aldehydes; Alzheimer disease prevention; Alzheimer' s Disease; American; Amination; Amines; Amyloid; Amyloid beta-Protein; Animals; Avena sativa; Biological; Biological Availability; Biological Markers; Blood; Blood Platelets; Body Surface Area; Brain; Buckwheat; Cause of Death; Chemicals; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials; Cognitive; Collaborations; Complete Blood Count; Data; Dendritic cell activation; Development; Diffuse; Disease; Disease Progression; Dose; Drug Kinetics; Evaluation; Functional disorder; Goals; High Density Lipoproteins; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Inflammation; Injury; Kidney; Kinetics; Ligands; Lipid Peroxidation; Lipid Peroxides; Liver; Lysine; Malondialdehyde; Measures; Memory impairment; Metabolic; Metabolism; Metals; Monitor; Mus; Muscle; N-methylacetamide-oxotremorine M; Natural Products; No-Observed-Adverse-Effect Level; Nutritional; Oral; Oxidation-Reduction; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Penetrance; Peptides; Pharmacodynamics; Plasma; Post-Translational Protein Processing; Preventive; Preventive treatment; Process; Production; Prostaglandin-Endoperoxide Synthase; Proteins; Reactive Oxygen Species; Regimen; Research; Safety; Seeds; Short-Term Memory; Spinal Puncture; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Toxic effect; Toxicology; Transgenic Mice; Validation; adduct; age related; amyloid peptide; base; clinical toxicology; crosslink; curative treatments; cyclooxygenase 1; disorder prevention; effective therapy; efficacy study; experimental study; immunoreactivity; in vivo; manufacturing process; mild cognitive impairment; mitochondrial dysfunction; neurotoxic; neurotoxicity; novel; pre-clinical; preclinical development; prevent; protein folding; protein function; small molecule; tau Proteins; volunteer

Approximately 5.2 million Americans are affected by Alzheimer’s disease (AD), and up to 13 million will be affected by 2050. At present, there is no preventive or curative treatment for AD or in age-related cognitive decline and clinical trials of cognitive-modifying compounds have not succeeded in identifying an effective treatment. Despite a lot of efforts, no candidates are available to slow down the development or even cure this devastating disease. Although most of the efforts are focusing on the amyloid and the tau pathways, we have taken a different approach and targeted oxidative stress. Oxidative stress is a major pathogenic mechanism that underlies both the pre-clinical development and subsequent progression of AD, and one that could potentially be targeted preventively as well as therapeutically. Levels of reactive oxygen species (ROS) increase during inflammation, mitochondrial dysfunction, and metal redox cycling catalyzed by A, all processes associated with AD development. ROS-catalyzed lipid peroxidation generates bifunctional electrophiles (BFEs). We have shown that BFEs generated by oxidative stress accelerate Aß oligomerization, generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid-derived diffusible ligands. They inhibit proteosomal activity, cause mitochondrial dysfunction, and promote dendritic cell activation of T cells. Importantly, we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains, and correlate positively with both the CERAD plaque score and the Braak stage. We have found that 2-hydroxybenzylamine (2-HOBA) reacts 1,600-fold faster with BFEs than lysine, preventing protein modification in vitro and in vivo. Importantly, in hApoE4 transgenic mice, 2-HOBA inhibits all the effects of BFEs described above, and prevents working memory deficit. 2-HOBA, a natural product present in buckwheat seeds, has been developed for use in humans by Metabolic Technologies, Inc. (MTI, Ames, IA). The chemical, manufacturing and control data have been generated and pre-clinical pharmacology and toxicology data are currently being collected. In this project, we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics, metabolism, and safety of 2-HOBA. We also propose to establish brain penetrance of 2-HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins.

大约 520 万美国人患有阿尔茨海默病 (AD)，其中多达 13 到 2050 年，将有 100 万人受到影响。目前，AD 或 AD 尚无预防或治疗方法。 与年龄相关的认知衰退和认知修饰化合物的临床试验尚未发现 成功地找到了有效的治疗方法。尽管做出了很多努力，但仍然没有候选人 可以减缓这种毁灭性疾病的发展甚至治愈这种疾病。虽然大多数 我们的努力集中在淀粉样蛋白和 tau 通路上，我们采取了不同的方法 方法和有针对性的氧化应激。 氧化应激是临床前的主要致病机制 AD 的发生和随后的进展，以及可能成为目标的疾病 既可以预防，也可以治疗。活性氧 (ROS) 水平在 A 催化的炎症、线粒体功能障碍和金属氧化还原循环，所有过程 与 AD 的发展有关。 ROS催化的脂质过氧化产生双功能 亲电子试剂（BFE）。我们已经证明，氧化应激产生的 BFE 会加速 Aß 寡聚化，产生具有相似神经毒性和免疫反应性的寡聚物 淀粉样蛋白衍生的可扩散配体。它们抑制蛋白体活性，导致线粒体 功能障碍，并促进 T 细胞的树突状细胞活化。重要的是，我们已经证明 AD死后海马中蛋白质上的BFE加合物水平显着升高 人类大脑，并与 CERAD 斑块评分和 Braak 阶段呈正相关。 我们发现 2-羟基苄胺 (2-HOBA) 与 BFE 的反应速度快 1,600 倍 比赖氨酸更能防止蛋白质在体外和体内的修饰。重要的是，在 hApoE4 转基因小鼠中，2-HOBA 抑制上述 BFE 的所有作用，并阻止工作 记忆力不足。 2-HOBA 是荞麦种子中的天然产物，已开发用于 人类由 Metabolic Technologies, Inc.（MTI，艾姆斯，爱荷华州）开发。化学、制造和 对照数据已生成，临床前药理学和毒理学数据已生成 目前正在收集中。在这个项目中，我们建议进行单次和多次递增剂量 表征 2-HOBA 的药代动力学、代谢和安全性所需的研究。我们 还建议建立 2-HOBA 的脑外显率并确定它是否会降低 蛋白质氧化修饰的血液和脑脊液标记。