Glutamatergic Treatments for Parkinson’s Disease

Parkinson’s disease is characterized by the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) projecting to the striatum and resulting motor and non-motor symptoms. The current knowledge demonstrates that the activity of glutamatergic signals from the cortex to the striatum is strictly regulated during the progression of the disease and indicates that modulation of synaptic transmission at the glutamatergic synapse represents a major target to rescue the altered neurotransmission. Molecular and functional alterations of glutamate receptors in experimental models of Parkinson’s disease as well as in patients have been demonstrated and several studies have been performed by using receptor antagonists/modulators. In particular, compounds targeting N-methyl-d-aspartatetype (NMDA) glutamate receptors and specific subtypes of metabotropic glutamate receptors (mGluR) have been tested both in preclinical and clinical studies. At present, amantadine, a low-affinity non-competitive NMDA receptor antagonist, represents a recommended add-on agent to decrease the dyskinetic motor complications of the dopaminergic therapy. The chapter will describe advances in basic research, preclinical and clinical studies in the attempt of identifying innovative strategies for the modulation of glutamate receptors in Parkinson’s disease. Overall, these results indicate that modulation of the glutamatergic system remains one of the promising pharmacological strategies in the field.