Przedborski Serge, Vila Miquel
Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology, Columbia University, New York, New York 10032, USA.
Ann N Y Acad Sci. 2003 Jun;991:189-98.
Experimental models of dopaminergic neurodegeneration play a critical role in our quest to elucidate the cause of Parkinson's disease (PD). Despite the recent development of "genetic models" that have followed upon the discovery of mutations causing rare forms of familial PD, toxic models remain at the forefront when it comes to exploring the pathogenesis of sporadic PD. Among these, the model produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has a competitive advantage over all other toxic models because once this neurotoxin causes intoxication, it induces in humans a syndrome virtually identical to PD. For the past two decades, the complex pharmacology of MPTP and the key steps in the MPTP neurotoxic process have been identified. These molecular events can be classified into three groups: First, those implicated in the initiation of toxicity, which include energy failure due to ATP depletion and oxidative stress mediated by superoxide and nitric oxide; second, those recruited subsequently in response to the initial neuronal perturbations, which include elements of the molecular pathways of apoptosis such as Bax; and, third, those amplifying the neurodegenerative insult, which include various proinflammatory factors such as prostaglandins. Herein, these different contributing factors are reviewed, as is the sequence in which it is believed these factors are acting within the cascade of events responsible for the death of dopaminergic neurons in the MPTP model and in PD. How to target these factors to devise effective neuroprotective therapies for PD is also discussed.
多巴胺能神经退行性变的实验模型在我们探寻帕金森病（PD）病因的过程中发挥着关键作用。尽管在发现导致罕见形式家族性PD的突变后，“遗传模型”有了新发展，但在探索散发性PD的发病机制方面，毒性模型仍处于前沿地位。其中，神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）产生的模型比所有其他毒性模型都具有竞争优势，因为一旦这种神经毒素导致中毒，它会在人类中诱发一种几乎与PD相同的综合征。在过去的二十年里，MPTP的复杂药理学以及MPTP神经毒性过程中的关键步骤已被确定。这些分子事件可分为三类：第一类与毒性起始有关，包括因ATP耗竭导致的能量衰竭以及由超氧化物和一氧化氮介导的氧化应激；第二类是在最初的神经元扰动后被招募的，包括凋亡分子途径中的一些成分，如Bax；第三类是放大神经退行性损伤的，包括各种促炎因子，如前列腺素。在此，将对这些不同的促成因素进行综述，以及它们在MPTP模型和PD中导致多巴胺能神经元死亡的事件级联中发挥作用的顺序。还将讨论如何针对这些因素设计有效的PD神经保护疗法。
