Apocynin Neuroprotection in a Parkinson's Disease Model

罗布麻素在帕金森病模型中的神经保护作用

• 批准号: 7012858
• 负责人: JOHN L GOUDREAU
• 金额: $ 16.65万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012858
• 关键词: NAD(P)H dehydrogenase; Parkinson' s disease; antioxidants; brain disorder chemotherapy; disease /disorder model; drug screening /evaluation; enzyme inhibitors; histopathology; laboratory mouse; methylphenyltetrahydropyridine; neuropharmacology; neuroprotectants; neurotoxins; nonhuman therapy evaluation; nonsteroidal antiinflammatory agent; pharmacokinetics; phenone; substantia nigra

DESCRIPTION (provided by applicant): The goal of effective neuroprotective treatments in Parkinson's disease (PD) is to slow or halt the progressive degeneration of nigrostriatal dopamine (DA) neurons associated with deteriorating motor function. Emerging evidence suggests that microglial activation and inflammation-mediated oxidative stress are important mechanisms in the pathogenesis and propagation of the nigrostriatal DA neuronal damage seen in PD [4, 5]. As such, anti-inflammatory agents and, more specifically, inhibitors of inflammation-mediated oxidative stress are rational candidates for neuroprotective drugs in patients with PD. Apocynin, a selective inhibitor of NADPH-oxidase, can block the production of superoxide and oxygen free radicals that typically accompany inflammation [6, 7]. Apocynin has been used to prevent oxidative stress-mediated cell damage in several disease models [8-18], but has not been investigated in animal models of PD. The goal of this project is to provide predinical efficacy and safety data for the use of apocynin as a neuroprotective therapy in PD. To this end, we propose to determine the ability of apocynin to inhibit damage to nigrostriatal DA neurons in mice following chronic l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) exposure. We hypothesize that apocynin will protect nigrostriatal DA neurons from MPTP-induced neuronal damage by inhibiting NADPH-oxidase mediated production of oxygen free radicals in the substantia nigra. The following specific aims are proposed: 1. To provide preclinical pharmacokinetc and safety data for the chronic use ofapocynin as a neuroprotective compound in PD. 2. To provide preclinical efficacy data for apocynin as a neuroprotective compound in the chronic MPTP mouse model of PD. The completion of the proposed studies will provide the critical preclincal data that would facilitate direct translation ofapocynin into phase I clinical testing as a potential neuroprotective compound in PD. If successful, the novel neuroprotective strategy of NADPH-oxidase inhibition could be developed to slow secondary disease progression in patients with PD.

描述（由申请人提供）： 帕金森病 (PD) 有效神经保护治疗的目标是减缓或阻止与运动功能恶化相关的黑质纹状体多巴胺 (DA) 神经元的进行性退化。新的证据表明，小胶质细胞激活和炎症介导的氧化应激是 PD 中黑质纹状体 DA 神经元损伤的发病机制和传播的重要机制 [4, 5]。因此，抗炎药，更具体地说，炎症介导的氧化应激抑制剂是帕金森病患者神经保护药物的合理候选者。罗布麻素是 NADPH 氧化酶的选择性抑制剂，可以阻止通常伴随炎症的超氧化物和氧自由基的产生 [6, 7]。罗布麻宁已被用于预防多种疾病模型中氧化应激介导的细胞损伤[8-18]，但尚未在PD动物模型中进行研究。该项目的目标是为使用罗布麻宁作为帕金森病的神经保护疗法提供临床前疗效和安全性数据。为此，我们建议确定夹竹桃麻素抑制慢性 L-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 暴露的小鼠黑质纹状体 DA 神经元损伤的能力。我们假设罗布麻宁将通过抑制 NADPH 氧化酶介导的黑质中氧自由基的产生来保护黑质纹状体 DA 神经元免受 MPTP 诱导的神经元损伤。 提出以下具体目标： 1. 为长期使用夹竹桃麻素作为PD神经保护化合物提供临床前药代动力学和安全性数据。 2. 提供罗布麻宁作为神经保护化合物在慢性 MPTP PD 小鼠模型中的临床前疗效数据。 拟议研究的完成将提供关键的临床前数据，这些数据将有助于将夹竹桃麻素作为帕金森病的潜在神经保护化合物直接转化为 I 期临床测试。如果成功，可以开发新的 NADPH 氧化酶抑制神经保护策略来减缓 PD 患者的继发性疾病进展。