Apocynin Neuroprotection in a Parkinson's Disease Model

描述(由申请人提供)： 帕金森病(PD)有效的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。新出现的证据表明，小胶质细胞激活和炎症介导的氧化应激是帕金森病患者黑质纹状体DA神经元损伤的发病和传播的重要机制[4，5]。因此，抗炎药，更具体地说，炎症介导的氧化应激的抑制剂是帕金森病患者神经保护药物的合理候选药物。载脂蛋白是一种选择性的NADPH-氧化酶抑制剂，可以阻止通常伴随炎症产生的超氧化物和氧自由基的产生[6，7]。在几种疾病模型中，apocynin已被用于防止氧化应激介导的细胞损伤[8-18]，但尚未在帕金森病动物模型中进行研究。本项目的目的是为载脂蛋白在帕金森病神经保护治疗中的应用提供临床疗效和安全性数据。为此，我们建议确定载脂蛋白抑制慢性暴露于L-甲基-4-苯基-L，2，3，6-四氢吡啶所致小鼠黑质纹状体DA神经元损伤的能力。我们推测，载脂蛋白可能通过抑制NADPH-氧化酶介导的黑质氧自由基的产生而保护黑质纹状体DA神经元免受MPTP所致的神经元损伤。 提出了以下具体目标： 1.为帕金森病患者长期应用apocynin作为神经保护药物提供临床前药代动力学等安全数据。 2.为罗布麻素作为神经保护化合物在慢性MPTP小鼠帕金森病模型中的临床前疗效提供数据。 拟议研究的完成将提供关键的临床前数据，有助于将载脂蛋白直接转化为I期临床试验，作为一种潜在的帕金森病神经保护化合物。如果成功，可以开发抑制NADPH-氧化酶的新的神经保护策略来减缓帕金森病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.