Protective actions of the anti-inflammatory drug candidate 10-nitro-oleic acid in Parkinson’s disease

项目总结 帕金森氏病(PD)的有效疗法是一个未得到满足的需求，因为目前的治疗方法已经 事实证明，这对减缓或逆转疾病的发展是无效的。完全相同的 帕金森病患者选择性黑质纹状体细胞丢失的机制尚不清楚，但 越来越多的人一致认为氧化应激和神经炎症起着关键作用。在这 关于新的药理策略，基于依赖于Nrf2的抗氧化剂的激活， 组织修复反应，促炎症因子-kB依赖的细胞因子的抑制和 黏附分子的表达和NADPH氧化酶-2(NOX-2)的活性显示出良好的前景 帕金森病治疗的结果。新药候选10-硝基-油酸(10-NO2-OA)显示组织- 在多个临床前模型中的保护和抗炎作用，已清除5个阶段1 在107名受试者中进行人体试验，目前正在进行与慢性阻塞性肺疾病治疗相关的第二阶段研究 肺部和肾脏疾病。值得注意的是，我们刚刚发现10-NO2-OA很容易跨越 血脑屏障。从这一观点来看，现在假设10-NO2-OA访问 抑制帕金森病的氧化应激和神经退行性变 通过调节NRF2和NF-kB依赖的基因表达和抑制PRO-KB的表达 炎症性NADPH氧化酶-2(Nox-2)活性。然后，我们建议研究临床前模型。 目的：明确10-NO2-OA在限制帕金森病发病机制中的作用。这样做的理由是 该项目是在大脑中建立治疗性的10-NO2-OA浓度将 促进有益的多效性组织保护反应，从而代表一种安全和 有效的药物策略，以防止多因素疾病的进展，如帕金森病。这个 这项建议的目标是：1)确定10-NO2-OA的神经保护潜力 核转录因子Nrf2和核因子-kB依赖的基因表达调控及对NOx-2活性的抑制 帕金森病体外模型的建立，2)评价10-NO_2-OA在中脑的PK及其神经保护作用 对大鼠鱼藤酮帕金森病模型的影响。圆满完成拟议的研究计划 可以通过揭示一种新的药物策略来缓解 帕金森病的经济和临床负担。 。

PROJECT SUMMARY An effective cure for Parkinson's disease (PD) is an unmet need, since current treatments have proved ineffective to slow down or reverse the progression of the disease. The exact mechanisms of the selective nigrostriatal cell loss in PD are still poorly understood, but there is an increasing consensus that oxidative stress and neuro-inflammation play a critical role. In this regard, new pharmacological strategies, based on the activation of Nrf2-dependent antioxidant, tissue-repair responses, the inhibition of pro-inflammatory NF-kB-dependent cytokine and adhesion molecule expression, and NADPH oxidase-2 (NOX-2) activity, have shown promising results in PD therapy. The new drug candidate 10-nitro-oleic acid (10-NO2-OA) displays tissue- protective and anti-inflammatory actions in multiple preclinical models, has cleared 5 Phase 1 human trials in 107 subjects, and is now in Phase II studies related to the treatment of chronic pulmonary and renal diseases. Notably, we have just discovered that 10-NO2-OA readily cross the blood-brain barrier. From this insight, it is now hypothesized that 10-NO2-OA accesses the nigrostriatal region of the brain and will inhibit oxidative stress and neurodegeneration in PD through modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of pro- inflammatory NADPH oxidase-2 (Nox-2) activity. Then, we propose to study preclinical models to define the efficacy of 10-NO2-OA in limiting the pathogenesis of PD. The rationale for this project is that the establishment of therapeutic 10-NO2-OA concentrations in the brain will promote beneficial pleiotropic tissue-protective responses, thus representing a safe and effective drug strategy to prevent the progression of a multi-factorial disease such as PD. The goals of this proposal are: 1) Define the neuroprotective potential of 10-NO2-OA through the modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of Nox-2 activity in an in vitro model of PD, 2) Evaluate the PK of 10-NO2-OA in the midbrain and its neuroprotective effects in a rotenone model of PD in rat. Successful completion of the proposed research plan can have a significant positive impact by revealing a new pharmacological strategy to alleviate the economic and clinical burden of PD. .