Potential neuroprotection mechanisms in PD: focus on dopamine agonist pramipexole

Background: The death of dopaminergic neurons in Parkinson's disease (PD) appears to have various causes, including oxidative stress, excitotoxicity, mitochondrial dysfunction (and associated apoptosis), ubiquitin/proteasomal dysfunction, and inflammation, any of which could in principle be the therapeutic target of a neuroprotective drug. The biology of dopaminergic neurons offers further potential targets, involving neurotrophic factors, dopamine-neuron genes, and even neurogenesis. Objective: To outline each hypothetical neuroprotective mechanism, the evidence suggesting its relevance to PD, and the research on pharmacologic intervention. Methods: A PubMed search was conducted to identify relevant preclinical and clinical literature published between 1989 and 2009. Additional articles were identified by reviewing the reference lists of papers selected in the original search. To circumscribe the survey and facilitate consideration of the conditions required for a neuroprotective effect, emphasis was placed on a single drug class, dopamine agonists, and in particular pramipexole. Review of the field: In a variety of in vitro and in vivo PD models, pramipexole exhibited preclinical evidence of neuroprotective actions of all hypothesized types, and in human neuroimaging studies it slowed the rate of loss of markers of dopaminergic function, consistent with drug-conferred neuroprotection in PD itself. Interpretation of the preclinical data was hampered by differences among models and by uncertainties concerning each model's mimicry of PD. Overall, the identified neuroprotection almost always required pretreatment (i.e., before insult) and high drug concentration. Interpretation of the clinical data was hampered by absence of placebo control and of a direct measure of neuroprotection. Conclusions: Although the evidence is promising, neuroprotection in PD remains an elusive goal. In whatever form it emerges, neuroprotective therapy would be a strong argument against deferring PD treatment until symptoms are a significant life impediment, and thus would add urgency to early PD identification.