Complex Isopathic Drug Development for Neuroprotection

描述(申请人提供)：中风是第三大死因 在美国，也是导致残疾的主要原因。的疾病 非导弹头部创伤引起的神经退行性变和脑损伤 在美国，每年有近50万人入院。虽然病原学 可能不同，但涉及相同的解剖和生理底物 情况，包括缺血和缺氧损伤以及兴奋性物质的释放 氨基酸，尤指病态或受损细胞中的谷氨酸。我们一直在 利用体外和体内实验性脑缺血模型和细胞模型 谷氨酸毒性的研究，以研究这些神经元损伤的机制，并 针对神经变性的早期干预治疗策略。 一种尚未被探索的有希望的策略是使用低剂量的 增强细胞耐受性和恢复能力的化学物质。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 那些系统。低剂量染毒对细胞功能的刺激作用 化学品通常可以减轻高剂量产生的不利影响。这 这一现象在毒理学领域得到了广泛的研究，称为 “兴奋效应”是某些类型观察到的效应的理论基础。 顺势而为(具体地说是等位疗法)。虽然矛盾的剂量效应一直是 它们还没有在多种细胞类型和门中得到证实 神经退行性变检查。在初步研究中，我们已经证明 这种保护作用发生在暴露于低和超低辐射的神经细胞中 谷氨酸和NMDA的剂量以及一定剂量的谷氨酸/钾 联合用药可在体内预防中风。 这个项目的目标是使用神经元培养系统来识别 四种神经毒素的最佳保护剂量及不同作用方式 机制-谷氨酸/钾制剂，NMDA，放线菌亚胺， MPPepsilon，这些的组合。我们还将开始初步检查 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可供使用的系统方法 并将为科学研究奠定基础 神经退行性变和脑内顺势和等位药物的研究进展 受伤。

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.