α-Synuclein- and MPTP-Generated Rodent Models of Parkinson's Disease and the Study of Extracellular Striatal Dopamine Dynamics: A Microdialysis Approach
α-Synuclein- and MPTP-Generated Rodent Models of Parkinson's Disease and the Study of Extracellular Striatal Dopamine Dynamics: A Microdialysis Approach
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DOI：
10.2174/187152710791556177
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发表时间：
2010-08-01
影响因子：
3
通讯作者：
Miele, Egidio
中科院分区：
文献类型：
--
作者：
Bazzu, Gianfranco;Calia, Giammario;Miele, Egidio
帕金森病（PD）的经典动物模型依赖于使用神经毒素，包括1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）、6-羟基多巴胺以及最近的农用化学品百草枯和鱼藤酮，以消耗多巴胺（DA）。这些神经毒素在不同的动物物种引起运动缺陷，虽然MPTP未能诱导大鼠的多巴胺能神经变性。为了更好地再现PD的关键特征，特别是神经变性的进行性，基于α-突触核蛋白（α-syn）和PD之间的遗传和神经病理学联系，已经开发了替代PD模型。在体内微透析被用来研究细胞外纹状体DA动力学MPTP和α-syn产生的啮齿动物模型的PD。急性和亚急性MPTP中毒小鼠纹状体DA释放延长。这种DA释放可能被认为是MPTP诱导的纹状体DA耗竭和黑质神经元死亡的第一步，主要通过活性氧的产生。虽然MPTP诱导DA减少，但神经化学和运动恢复在治疗结束后立即开始，这表明代偿机制被激活。因此，PD的MPTP小鼠模型可能不适合于密切再现人类疾病的特征和预测潜在的长期治疗效果，在纹状体细胞外DA和行为结果方面。相比之下，α-syn产生的PD大鼠模型在黑质病变诱导期间不会大量释放纹状体DA，而是以基线DA的长期降低和尼古丁诱导的透析液DA水平升高为特征。这些结果表明，一个稳定的黑质纹状体病变缺乏多巴胺能神经化学恢复。因此，alpha-syn大鼠模型再现了PD的初始阶段和缓慢发展，运动功能具有时间依赖性损伤。本文将描述上述实验PD模型，并证明其表征微透析的效用。
The classical animal models of Parkinson's disease (PD) rely on the use of neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine and, more recently, the agricultural chemicals paraquat and rotenone, to deplete dopamine (DA). These neurotoxins elicit motor deficits in different animal species although MPTP fails to induce a significant dopaminergic neurodegeneration in rats. In the attempt to better reproduce the key features of PD, in particular the progressive nature of neurodegeneration, alternative PD models have been developed, based on the genetic and neuropathological links between alpha-synuclein (alpha-syn) and PD. In vivo microdialysis was used to investigate extracellular striatal DA dynamics in MPTP- and alpha-syn-generated rodent models of PD. Acute and sub-acute MPTP intoxication of mice both induce prolonged release of striatal DA. Such DA release may be considered the first step in MPTP-induced striatal DA depletion and nigral neuron death, mainly through reactive oxygen species generation. Although MPTP induces DA reduction, neurochemical and motor recovery starts immediately after the end of treatment, suggesting that compensatory mechanisms are activated. Thus, the MPTP mouse model of PD may be unsuitable for closely reproducing the features of the human disease and predicting potential long-term therapeutic effects, in terms of both striatal extracellular DA and behavioral outcome. In contrast, the alpha-syn-generated rat model of PD does not suffer from a massive release of striatal DA during induction of the nigral lesion, but rather is characterized by a prolonged reduction in baseline DA and nicotine-induced increases in dialysate DA levels. These results are suggestive of a stable nigrostriatal lesion with a lack of dopaminergic neurochemical recovery. The alpha-syn rat model thus reproduces the initial stage and slow development of PD, with a time-dependent impairment in motor function. This article will describe the above experimental PD models and demonstrate the utility of microdialysis for their characterization.