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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.
AuthorsKari A Johnson, P Jeffrey Conn, Colleen M Niswender
JournalCNS & neurological disorders drug targets (CNS Neurol Disord Drug Targets) Vol. 8 Issue 6 Pg. 475-91 (Dec 2009) ISSN: 1996-3181 [Electronic] United Arab Emirates
PMID19702565 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Antiparkinson Agents
  • Excitatory Amino Acid Antagonists
  • Receptors, Glutamate
Topics
  • Animals
  • Antiparkinson Agents (pharmacology, therapeutic use)
  • Excitatory Amino Acid Antagonists (pharmacology, therapeutic use)
  • Humans
  • Models, Biological
  • Neural Pathways (drug effects, metabolism)
  • Parkinson Disease (drug therapy, metabolism, pathology)
  • Receptors, Glutamate (drug effects, metabolism)

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