Complex Isopathic Drug Development for Neuroprotection

用于神经保护的复杂同向药物开发

• 批准号: 6431273
• 负责人: WAYNE B JONAS
• 金额: $ 16.01万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6431273
• 关键词: alternative medicine; aspartate; brain injury; cycloheximide; dosage; drug design /synthesis /production; excitatory aminoacid; glutamates; laboratory rat; methylphenyltetrahydropyridine; neural degeneration; neurons; neuropharmacology; neuroprotectants; neurotoxins; potassium; tissue /cell culture

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and the leading cause of disability. Diseases of neurodegeneration and brain damage from non-missile head trauma account for nearly 500,000 hospital admissions in the U.S. annually. Although the etiology may differ, the same anatomic and physiologic substrates are involved in these conditions, including ischemia and hypoxic injury and the release of excitatory amino acids, especially glutamate from diseased or damaged cells. We have been using in vitro and in vivo models of experimental ischemia and cellular models of glutamate toxicity to examine these mechanisms of neuronal injury, and to target early intervention treatment strategies for neurodegeneration. One promising strategy that has not been explored is the use of low doses of chemicals to enhance cell tolerance and recovery. High doses of toxic chemicals will inhibit and kill biological systems, while low doses frequently stimulate those systems. Stimulation of cell function by exposure to low doses of chemicals can often mitigate the adverse effects produced by high doses. This phenomenon has been extensively studied in the area of toxicology called "hormesis" and is the theoretical basis for the observed effects in some types of homeopathy (specifically isopathy). While paradoxical dose effects have been demonstrated across multiple cell types and phyla they have not yet been examined in neurodegeneration. In preliminary research we have demonstrated that protective effects occur in neuronal cells exposed to low and ultra-low doses of glutamate and NMDA and that certain doses of glutamate/potassium combinations protect against stroke in vivo. The objective of this project is to use neuronal culture systems to identify the optimal protective doses and of four neurotoxins that work by different mechanisms - a glutamate/potassium preparation, NMDA, cycloheximide, MPPepsilon, a combination of these. We will also begin preliminary examination of selected mechanisms of the optimal protective combination and dose. This project will, for the first time, have produced a systematic approach for use of protective hormesis and will lay the foundation for the scientific development of homeopathic and isopathic drugs in neurodegeneration and brain injury.

描述（由申请人提供）：中风是第三大死亡原因 是导致残疾的主要原因。疾病 非导弹头部创伤造成的神经变性和脑损伤 美国每年有近50万人入院。虽然病因 可能有所不同，但在这些过程中涉及相同的解剖学和生理学基质。 条件，包括缺血和缺氧损伤以及兴奋性神经递质的释放。 氨基酸，特别是来自患病或受损细胞的谷氨酸。我们一直 使用实验性局部缺血的体外和体内模型和细胞模型 谷氨酸毒性的研究，以检查神经元损伤的这些机制，并 针对神经退行性疾病的早期干预治疗策略。 一种尚未探索的有希望的策略是使用低剂量的 化学物质，以提高细胞的耐受性和恢复。高剂量的有毒化学物质 会抑制和杀死生物系统，而低剂量经常刺激 这些系统。通过暴露于低剂量的 化学品往往可以减轻高剂量产生的不利影响。这 这种现象在毒理学领域得到了广泛的研究， “兴奋效应”，是在某些类型的观察效果的理论基础 顺势疗法（homeopathy）。虽然矛盾的剂量效应一直是 在多种细胞类型和门中证明了它们尚未被 在神经退行性变中检查。在初步研究中，我们已经证明， 保护作用发生在暴露于低浓度和超低浓度的 一定剂量的谷氨酸盐和NMDA以及一定剂量的谷氨酸盐/钾 组合在体内防止中风。 本项目的目的是利用神经元培养系统， 最佳保护剂量和四种神经毒素， 机制-谷氨酸/钾制剂，NMDA，放线菌酮， MPPeppeptide，这些的组合。我们也将开始初步审查 最佳保护组合和剂量的选定机制。这 该项目将首次产生一种系统的方法， 保护性兴奋效应，并将为科学的 神经变性和脑中顺势疗法和等顺势疗法药物的发展 损伤