Glutamate-Based Approaches

Glutamate-based therapeutic approaches are being explored as potential treatments for both PD symptoms and L-DOPA-induced dyskinesia. These therapies aim to re-calibrate the function of the basal ganglia following loss of dopaminergic innervation. This may normalize signaling through the motor circuit to lead to symptomatic benefit. Glutamate-based therapies are also being explored as potential disease-modifying therapies, as there are indications that reducing glutamatergic function may reduce the excitotoxic cell death implicated in PD.

Therapeutic development includes targeting both ionotropic and metabotropic glutamate receptors (Marino and Conn, 2006), as well as the N-methyl-D-aspartate receptor (NMDA). In fact, it is thought that the low-affinity NMDA receptor channel blocker amantadine may derive its mild anti-parkinsonian activity by interfering with increased glutamate signaling in the basal ganglia. Selective targeting of NMDA subunits is also being explored for therapeutic development.

Because of their specific neuroanatomical localization within the basal ganglia and role in regulating excitability in the motor circuit, metabotropic glutamate receptors are being investigated as potential targets for symptomatic therapies for Parkinson’s disease. Significant efforts are underway to develop selective modulators of mGluR4 receptors for Parkinson’s disease (Marino and Conn, 2006) and a clinical trial is currently underway to investigate an mGluR5 antagonist as a treatment for dyskinesia.