GLUTAMATE ANTAGONISTS FOR PARKINSONS-DISEASE - RATIONALE FOR USE AND THERAPEUTIC IMPLICATIONS

Parkinson's disease results from degeneration of dopaminergic neurons within the substantia nigra. The treatment of the disease was revoluti onised by the introduction of dopamine replacement therapy. However, i t has become increasingly clear that prolonged administration of dopam ine agonists results in the onset of a spectrum of serious adverse eff ects, including dyskinesias. Accordingly, there is great interest in a lternative strategies for the treatment of this condition. It is now r ealised that the loss of nigral dopamine cells and subsequent lowering of striatal dopamine levels causes a chain of pathophysiological even ts within the basal ganglia. One of the most prominent of these events is an elevation in the level of glutamate-mediated transmission withi n the striatum and the output structures of the basal ganglia. A range of glutamate antagonists has been shown to alleviate symptoms in anim al models of Parkinson's disease. Antagonists of both the N-methyl-D-a spartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propion ic acid (AMPA) subtypes of the glutamate receptor result in an improve ment in motor behaviour in experimental animal models. However, system ic administration of NMDA antagonists is also associated with several adverse effects, the most common being ataxia, sedation and cognitive impairments. These problems can potentially be overcome by the use of antagonists that are selective for the subtypes of NMDA receptors whic h are preferentially expressed in the critical parts of the pathophysi ological circuitry. Glutamate antagonists are also known to have stron g neuroprotective effects. Consequently, administration of glutamate a ntagonists may slow the rate of loss of nigral dopaminergic neurons an d thus slow the progression of Parkinson's disease.