Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine
Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine
复制标题
DOI：
10.1016/j.bbr.2014.08.014
复制
发表时间：
2014-11-01
影响因子：
2.7
通讯作者：
Vital, Maria A. B. F.
中科院分区：
文献类型：
--
作者：
Barbiero, Janaina K.;Santiago, Ronise M.;Vital, Maria A. B. F.
大量证据表明，过氧化物酶体增殖激活受体（PPAR）激动剂可能改善帕金森病（PD）的一些病理特征。在本研究中，我们评估了ppar - α激动剂非诺贝特（100 mg/kg）和ppar - γ激动剂吡格列酮（30 mg/kg）在黑质内1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的帕金森大鼠模型中的作用。雄性Wistar大鼠用这两种药物预处理5天，然后输注MPTP。实验分为两部分。首先，术后第1、7、14、21天进行野外试验。第21、22天进行强迫游泳实验和双向主动回避任务。在研究的第二部分，神经毒素给药24小时后，进行免疫组织化学评估酪氨酸羟化酶活性。采用高效液相色谱法测定纹状体中多巴胺及其代谢物水平，荧光检测黑质致密部（SNpc）中caspase-3的激活情况。非诺贝特与吡格列酮均可预防由MPTP引起的低运动、抑郁样行为、学习和记忆障碍以及多巴胺能神经退行性变（多巴胺能神经元损失约33%）。非诺贝特和吡格列酮还可以防止caspase-3的激活增加，caspase-3是凋亡级联的效应酶，被认为是PD的病理特征之一。因此，PPAR激动剂可能有助于PD的治疗策略。(C) 2014 Elsevier B.V.版权所有
A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-alpha agonist fenofibrate (100 mg/kg) and PPAR-gamma agonist pioglitazone (30 mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24 h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD. (C) 2014 Elsevier B.V. All rights reserved.