Glutamate in Parkinson's disease: Role of antiglutamatergic drugs

In the brain, glutamatergic transmission plays a key role in the normal physiology of those systems that modulate motor activity (especially in the basal ganglia). In pathological conditions such as Parkinson's disease (PD), glutamatergic transmission is considerably affected, thereby contributing to the alterations involved in this disorder. Neurotransmitter alterations in direct and indirect nigro-striatal pathways occurring in PD are known to involve glutamatergic hyperactivity. It has been suggested that this hyperactive pattern plays a dual role: on one hand, it promotes excitotoxic events that contribute to the neurodegenerative process, while on the other hand, it contributes to the pathophysiology of dyskinesias and motor fluctuations that have been associated with the chronic use of levodopa (l-DOPA). Although l-DOPA remains the only standard treatment that offers significant improvement in Parkinsonian symptoms, its chronic use has been associated with the development of motor fluctuations and dyskinesias. Therefore, the design of new therapies directed to targets different from those classic dopaminergic ones is particularly relevant nowadays. Recently, interest has been growing in the development of new anti-glutamatergic drugs (AGD). Experimental and clinical evidence supports a considerable number of positive effects of AGD in PD, including reduction of Parkinsonian symptoms, as well as modulation of motor complications derived from dopaminergic therapy and also neuroprotective properties. The purpose of this review is to provide an updated review of antiglutamatergic therapies that have been tested in PD and its future role in the management of PD.