The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model: a Tool to Explore the Pathogenesis of Parkinson's Disease

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.