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棕榈酰乙醇酰胺在帕金森病动物模型中的神经保护活性。

Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease.

机构信息

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.

出版信息

PLoS One. 2012;7(8):e41880. doi: 10.1371/journal.pone.0041880. Epub 2012 Aug 17.

Abstract

The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated MPTP systemic toxicity, while PEA-induced neuroprotection seemed be partially PPARα-dependent. The effects of PEA on molecules typically involved in apoptotic pathways were also analyzed. Our results indicate that PEA protects against MPTP-induced neurotoxicity and the ensuing functional deficits even when administered once the insult has been initiated.

摘要

1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)治疗后发生的生化和细胞变化与特发性帕金森病(PD)非常相似。PD 的特征是多巴胺能黑质纹状体神经元的退化,导致运动障碍。胶质细胞的激活以及随之而来的神经炎症反应,越来越被认为是 PD 的一个突出的神经病理学特征。目前尚无有效的疾病修饰疗法。针对胶质细胞中负责神经炎症的信号通路,代表了一种有前途的新治疗方法,旨在保护 PD 中剩余的神经元。慢性给予棕榈酰乙醇酰胺(PEA,10mg/kg,腹腔注射),在 MPTP 注射(20mg/kg)后 24 小时开始,可防止 MPTP 诱导的黑质致密部酪氨酸羟化酶阳性神经元丢失。PEA 治疗可减少 MPTP 诱导的小胶质细胞激活、GFAP 阳性星形胶质细胞数量和 S100β过表达,并防止黑质中微管相关蛋白 2a、b-、多巴胺转运体-、nNOS 阳性细胞的改变。此外,慢性 PEA 逆转了 MPTP 相关的运动缺陷,这可以通过前脚爪步宽和错误百分比的分析来揭示。过氧化物酶体增殖物激活受体(PPAR)-α 基因敲除(PPAR-αKO)小鼠中 PPAR-α 的基因缺失加剧了 MPTP 的全身毒性,而 PEA 诱导的神经保护作用似乎部分依赖于 PPARα。还分析了 PEA 对通常涉及细胞凋亡途径的分子的影响。我们的结果表明,PEA 可防止 MPTP 诱导的神经毒性和随后的功能缺陷,即使在损伤已经开始时给予 PEA。

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