OASI Institute for Research and Care on Mental Retardation and Brain Aging (IRCCS), Neuropharmacology Section, 94018 Troina, Italy.
J Neuroinflammation. 2010 Nov 23;7:83. doi: 10.1186/1742-2094-7-83.
Current evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg(-1) daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP.
Ageing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomal dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP.
HCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in substantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons.
Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.
目前的证据表明，神经炎症在帕金森病（PD）的发病机制和基底神经节损伤的 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）模型中发挥作用。据报道，非甾体抗炎药（NSAIDs）减轻了 PD 啮齿动物模型中的 DA 能神经毒性。与这些发现一致，流行病学分析表明，某些 NSAIDs 可能预防或延缓 PD 的进展。然而，慢性 NSAID 治疗的一个严重障碍，特别是在老年人中，是胃、肾和心脏毒性。一氧化氮（NO）供体 NSAIDs 在保持母体化合物抗炎活性的同时具有更安全的特性。我们研究了氟比洛芬的 NO 供体衍生物[2-氟-α-甲基（1,1'-联苯）-4-乙酸 4-（亚硝基氧基）丁酯]，HCT1026（每天 30mg/kg 喂食于啮齿动物饲料中）在暴露于帕金森神经毒素 MPTP 的小鼠中的口服活性。
老年小鼠在接受 MPTP 治疗前 10 天开始用对照、氟比洛芬或 HCT1026 饮食喂养，并在整个实验期间继续喂养。纹状体高亲和力突触小体多巴胺摄取、用转棒评估运动协调、酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT）纤维染色、立体学细胞计数、免疫印迹和基因表达分析用于评估 MPTP 诱导的黑质纹状体 DA 能毒性和胶质细胞激活 1-40 天。
HCT1026 耐受性良好，不会引起任何可测量的毒性作用，而喂食氟比洛芬的小鼠则出现严重的胃肠道副作用。HCT1026 能有效对抗运动障碍，并逆转 MPTP 诱导的纹状体突触小体[3H]多巴胺摄取、TH 和 DAT 染色纤维以及黑质致密部（SNpc）TH+神经元丢失，而与对照饮食喂养的同龄小鼠相比。这些作用与纹状体和腹侧中脑内反应性巨噬细胞抗原-1（Mac-1）阳性小胶质细胞数量显著减少、诱导型一氧化氮合酶（iNOS）、Mac-1 和 NADPH 氧化酶（PHOX）表达减少以及黑质致密部 SNpc DA 能神经元 3-硝基酪氨酸（一种过氧亚硝酸盐指纹）下调有关。
口服 HCT1026 治疗具有安全的特性，对老年小鼠 MPTP 诱导的多巴胺能（DA 能）神经毒性、运动障碍和小胶质细胞激活具有显著疗效。HCT1026 为开发有效的 PD 神经保护策略提供了一种有前途的新方法。
