NEUROPROTECTIVE AGENTS FROM ORIENTAL MEDICINES

东方药物的神经保护剂

• 批准号: 6171435
• 负责人: TAE H OH
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171435
• 关键词: Animalia; Asia; alternative medicine; antioxidants; blood brain barrier; calcium flux; disease /disorder model; drug delivery systems; drug metabolism; drug screening /evaluation; folk medicine; glutamates; muscarinic receptor; neural degeneration; neuroprotectants; plant extracts; prodrugs; tissue /cell culture

DESCRIPTION: (Verbatim from the Applicant's Abstract) Ginsenoside Rg3, Cynandione A, and p-methoxy-trans-cinnamic acid (MCA), all isolated from Oriental herbal medicines, attenate neurotoxicity induced by glutamate in vitro. Neoline, isolated from Aconiti tubers, protects short-term memory, possibly by influencing central cholinergic transmission. The present proposal is designed to elucidate the mechanisms of their neuroprotective activities in vitro as well as in vivo. The latter mandates transport of these agents across the blood-brain barrier (BBB). Thus, prodrug approaches are adopted for brain delivery. Specfic Aim 1 tests a hypothesis that Rg3 and MCA exet neuroprotective activities by inhibiting Ca ++ influx by determining their efects on Ca++ influx in vitro. Aim 2 tests the hypothesis that Rg3, cynandione A and MCA exert neruoprotective activity by inhibiting neuronal apoptosis by assessing their effects on apoptosis and its markers in vitro and in vitro. Aim 3 tests a hypothesis that neoline ameliorates deficits in short-term memory by influencing central cholinergic transmission in the brain. As such, we will determine its effects on muscarinic receptors in vitro and in vivo as, and Ach levels in vivo. Aim 4 addresses issues involved in drug delivery across the BBB. To this end, we propose to synthesize a series of ester prodrugs of Rg3, and Rg3 analog (protopanaxadiol), and MCA. Aim 5 concerns with development of injectable formulations for these test compounds. Note that they are all water-insoluble. The overall goal of this proposal is to identify novel strategies of blocking oxidative stress, which is the primary cause of neuronal death or memory impairment linked to neurodegeneration. Results of this three-way collaborative research are significant in that: I) these curative s have been used in Asian societies for centuries; ii) no effective treatments are currently available for such adult neurodegenerative disorders as Alzheimer's disease or for injuries to the CNS/stroke; and iii) the progressive memory loss observed in various dementia is extremely debilitating, making any palliative measure a major clinical development.

描述：（逐字摘自申请人摘要）人参皂苷 Rg3， Cynandione A 和对甲氧基反式肉桂酸 (MCA)，全部分离自 东方草药，可减轻谷氨酸引起的神经毒性 体外。 Neoline，从乌头块茎中分离出来，可以保护短期记忆， 可能是通过影响中枢胆碱能传递。目前的建议 旨在阐明其神经保护活性的机制 体外和体内。后者要求将这些药剂运送到各地 血脑屏障（BBB）。因此，前药方法被用于大脑 送货。具体目标 1 检验 Rg3 和 MCA 执行的假设 通过确定其抑制 Ca ++ 流入来发挥神经保护活性 对体外 Ca++ 流入的影响。目标 2 检验以下假设：Rg3、cynandione A 和 MCA 通过抑制神经元凋亡发挥神经保护活性 评估它们对细胞凋亡及其标记物的体外和体外影响。目的 3 检验了新林通过以下方式改善短期记忆缺陷的假设： 影响大脑中枢胆碱能的传递。因此，我们将 确定其对体外和体内毒蕈碱受体和 Ach 的影响 体内水平。目标 4 解决整个药物输送过程中涉及的问题 BBB。为此，我们建议合成一系列Rg3的酯类前药， 和Rg3类似物（原人参二醇）和MCA。目标 5 关注发展 这些测试化合物的注射制剂。请注意，它们都是 不溶于水。该提案的总体目标是确定新颖的 阻断氧化应激的策略，氧化应激是神经元疾病的主要原因 与神经变性有关的死亡或记忆障碍。结果 三向合作研究的意义在于：I) 这些治疗方法 几个世纪以来一直在亚洲社会使用； ii) 没有有效的治疗方法 目前可用于治疗成人神经退行性疾病，例如 阿尔茨海默病或中枢神经系统损伤/中风； iii) 进步的 在各种痴呆症中观察到的记忆丧失是极其令人衰弱的，使得任何 姑息治疗是一项重大的临床发展。