Apocynin Neuroprotection in a Parkinson's Disease Model

描述（由申请人提供）： 帕金森病（PD）的有效神经保护治疗的目标是减缓或停止与运动功能恶化相关的黑质纹状体多巴胺（DA）神经元的进行性变性。新出现的证据表明，小胶质细胞活化和炎症介导的氧化应激是PD中观察到的黑质纹状体DA神经元损伤的发病机制和传播的重要机制[4，5]。因此，抗炎剂，更具体地说，炎症介导的氧化应激抑制剂是PD患者神经保护药物的合理候选物。夹竹桃素是NADPH氧化酶的选择性抑制剂，可阻断通常伴随炎症的超氧化物和氧自由基的产生[6，7]。夹竹桃麻素已用于预防几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。本项目的目的是提供使用夹竹桃麻素作为帕金森病神经保护治疗的临床疗效和安全性数据。为此，我们建议确定夹竹桃麻素抑制慢性1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）暴露后小鼠黑质纹状体DA神经元损伤的能力。我们推测夹竹桃麻素将通过抑制NADPH氧化酶介导的黑质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。 建议的具体目标如下： 1.为长期使用法泊昔宁作为PD的神经保护剂提供临床前药效学和安全性数据。 2.提供夹竹桃麻素作为神经保护化合物在慢性MPTP小鼠PD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，这将有助于将ofapocynin直接转化为I期临床试验，作为PD中潜在的神经保护化合物。如果成功的话，NADPH氧化酶抑制的新的神经保护策略可以被开发来减缓PD患者的继发性疾病进展。

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.