Glutamate receptors as therapeutic targets for Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD.

Figure 1. Basal ganglia circuitry in normal and disease states

Shown is a simplified schematic diagram of the direct and indirect pathways of the basal ganglia, regulation of the circuitry by dopaminergic projections from the substantia nigra pars compacta (SNc, shown in gray), and alterations contributing to the motor dysfunctions characteristic of Parkinson’s disease. The caudate and putamen collectively comprise the striatum in humans. In this figure, black projections are inhibitory (GABAergic) and red projections are excitatory (glutamatergic). Blue projections are dopaminergic. A. Within the direct pathway, GABAergic projections inhibit function of the basal ganglia output nuclei, which consist of the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr). These output nuclei send inhibitory projections to the thalamus, which regulates excitatory output to the cortex. Dopaminergic neurons (blue dashed line) arising in the SNc project to D₁-expressing neurons in the putamen area of the striatum that give rise to the direct pathway, and stimulate transmission through the direct pathway. B. Within the polysynaptic indirect pathway, striatopallidal projections from the putamen project to the external segment of the globus pallidus (GPe); inhibitory projections from the GPe then project to the GPi and subthalamic nucleus (STN). Dopaminergic neurons arising in the SNc project to D₂-receptor expressing neurons in the striatum that give rise to the indirect pathway and reduce activity of the indirect pathway (blue dashed line). The STN sends excitatory projections to the output nuclei, balancing the inhibitory tone mediated by the direct pathway and balancing the level of inhibition of the thalamus, which modulates excitation of the motor areas of the cortex. C. In PD, loss of dopaminergic neurons in the SNc (depicted as a change in color of the SNc from gray to white) results in too little inhibitory transmission via the direct pathway and too much inhibitory tone at the striatopallidal synapse, resulting in increased excitation of the output nuclei via the STN. The overall effect of the loss of dopamine neurons is too little inhibition of the output nuclei via the direct pathway and too much excitation from the indirect pathway. This enhanced excitation of the SNr and GPi is manifested as enhanced GABAergic tone at the level of the thalamus and too little excitation of motor areas of the cortex.

Figure 2. mGluR localization in the basal ganglia

The major nuclei of the basal ganglia are shown and the localization of various mGluR subtypes that are relevant to PD therapeutics is highlighted. Excitatory projections are represented as white arrows and inhibitory projections are represented as black arrows. Overall, the effect of group I mGluR activation (green and purple circles) is to counteract the effects of dopamine, particularly by increasing activity through the indirect pathway. Group II mGluRs (yellow circles) reduce glutamate release at several key synapses including the corticostriatal, STN-SNc, and STN-SNr synapses. Group III mGluRs (orange circles), including mGluRs 4, 7 and 8, are expressed at striatopallidal (predominantly mGluR4; activation of this receptor inhibits GABAergic transmission in the GPe) and the STN-SNr synapses. (GPe, external segment of globus pallidus; STN, subthalamic nucleus; GPi, internal segment of globus pallidus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta. Adapted from Conn et al., 2005 and Wichmann & DeLong, 1996.)