Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease

Abstract

Current drugs used in the treatment of Parkinson's disease (PD), for example, L-DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long-term use is associated with the appearance of adverse effects such as L-DOPA-induced dyskinesia. Much emphasis has therefore been placed on finding alternative non-dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre-synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD.

Figure 1

Schematic representation of the parkinsonian basal ganglia motor loop, showing the location of group III metabotropic glutamate (mGlu) receptors. The loss of striatal dopamine innervation following substantia nigra pars compacta (SNc) degeneration in Parkinson's disease (PD) produces opposing downstream changes in firing of the two main basal ganglia pathways. Thick lines indicate overactive pathways; thin lines indicate underactive pathways; dotted lines indicate degenerated pathways. In the direct pathway, loss of dopamine D1-like receptor stimulation reduces firing of GABAergic striatal efferents to the substantia nigra pars reticulata (SNr), while in the indirect pathway, loss of inhibitory D2-like receptor stimulation leads to increased firing in the GABAergic striatopallidal pathway, which in turn inhibits GABAergic drive to the subthalamic nucleus (STN), leading to increased firing of the glutamatergic STN efferents to the SNr and SNc. The increased glutamatergic innervation of the SNr ultimately drives inhibition of thalamocortical feedback, resulting in the motor deficits seen in PD, while the increased glutamatergic innervation in the SNc may contribute to the progressive SNc degeneration. Group III mGlu receptors (mGlu4, 7 or 8), indicated by black stars, are found on pre-synaptic terminals of intrinsic basal ganglia pathways where their activation may serve to restrict transmitter release. Receptor subtypes indicated in bold have been confirmed as functional, while those in red have been shown to lack function. DA, dopamine; Glut, glutamate.

Figure 2

Putative mechanisms underlying the protection of dopaminergic substantia nigra pars compacta (SNc) neurones following group III metabotropic glutamate (mGlu) receptor activation. Activation of group III mGlu receptors located at three different sites in the glutamatergic subthalamonigral synapse may underlie the protection of dopaminergic SNc neurones. (i) Activation of pre-synaptic mGlu4 or mGlu7 receptors will restrict the pre-synaptic Ca²⁺ entry required for glutamate release leading in turn to reduced synaptic glutamate levels and reduced stimulation of post-synaptic NMDA receptors. The resultant reduction in Ca²⁺ entry into SNc neurones is proposed to reduce excitotoxic damage. (ii) Activation of glial mGlu4, 7 or 8 receptors may lead, via activation of MAP kinase or elevation of the antioxidant reduced glutathione (GSH) levels, to increased glutamate uptake via GLT-1 or GLAST glutamate transporters, further reducing synaptic glutamate levels. Activation of glial receptors may also reduce the production of inflammatory mediators, such as chemokines, that in turn will reduce the inflammatory stress upon SNc neurones. (iii) Activation of mGlu4 or mGlu8 receptors on SNc neurones directly may lead to increased microtubule stabilization through a MAP kinase-dependent pathway. One or more of these events may contribute to the overall neuroprotective effects of group III mGlu receptor activation. G, glutamate; MAP kinase, mitogen-activated protein kinase.