Biochemical Society Transactions

Brain Disorders Across the Lifespan: Translational Neuroscience from Molecule to Man

Glutamatergic pathways as a target for the treatment of dyskinesias in Parkinson's disease

M. Angela Cenci

Abstract

PD (Parkinson's disease) is characterized by some typical motor features that are caused by striatal dopamine depletion and respond well to dopamine-replacement therapy with L-dopa. Unfortunately, the majority of PD patients treated with L-dopa develop abnormal involuntary movements (dyskinesias) within a few years. The mechanisms underlying the development of LIDs (L-dopa-induced dyskinesias) involve, on one hand, a presynaptic dysregulation of dopamine release and clearance and, on the other hand, an abnormal postsynaptic response to dopamine in the brain. There is a large amount of evidence that these dopamine-dependent mechanisms are modulated by glutamatergic pathways and glutamate receptors. The present article summarizes the pathophysiological role of glutamatergic pathways in LID and reviews pre-clinical and clinical results obtained using pharmacological modulators of different classes and subtypes of glutamate receptors to treat parkinsonian dyskinesias.

  • chorea
  • drug-induced movement disorder
  • dyskinesia
  • dystonia
  • glutamatergic pathway
  • neurodegenerative disease
  • Parkinson’s disease

Footnotes

  • Brain Disorders Across the Lifespan: Translational Neuroscience from Molecule to Man: An Independent Meeting held at University College Cork, Ireland, 12–13 September 2013. Organized and Edited by Eoin Fleming (University College Cork, Ireland).

Abbreviations: AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; iGluR, ionotropic glutamate receptor; LID, L-dopa-induced dyskinesia; mGluR, metabotropic glutamate receptor; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA, N-methyl-D-aspartate; 6-OHDA, 6-hydroxydopamine; PAM, positive allosteric modulator; PD, Parkinson’s disease; PET, positron-emission tomography; STN, subthalamic nucleus

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