Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease

Abstract

During the last 20 years, an enormous research effort and hundreds of millions of dollars have been spent attempting to develop and prove that drugs may slow the rate of progression of Parkinson disease (PD). At the time of writing, no drug has yet satisfied the rigorous criteria set by clinicians and licensing authorities for a neuroprotective agent. Despite this apparent failure, numerous important lessons have been learned, and some areas for optimism have emerged. Dopaminergic drugs have, for 40 years, been the basis for the treatment of the predominant early motor features of PD. Several of these drugs have also demonstrated an ability to protect cells, including neurons, against a range of toxins that are of relevance to the pathogenesis of PD. Some have entered clinical trials for neuroprotection, and a few have produced a positive result according to the endpoint selected. The interpretation of these trials is the subject of some debate. A pattern has emerged in these and other clinical trials, which has lead to a novel concept for neuroprotection, and that is simply to treat early rather than delay. The basis for this may lie in the support of basal ganglia compensatory mechanisms and the restoration of normal dopaminergic transmission.