Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys.
Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs have been proposed to relieve PD symptoms and decrease dyskinesias. Metabotropic glutamate receptors are topics of recent interest in PD. This study investigated the effects of the metabotropic glutamate receptors type 5 (mGluR5) antagonists MPEP and MTEP on motor behavior in monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD and treated with L-Dopa the gold standard therapy. Six Macaca fascicularis MPTP monkeys were initially treated repeatedly with L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores but also induced dyskinesias. Then, a dose-response of MPEP and MTEP (1.5-30 mg/kg) administered 15 and 30 min respectively prior to L-Dopa, showed that the antiparkinsonian activity of L-Dopa was generally maintained as measured with locomotion and antiparkinsonian scores as well as the onset and duration of the L-Dopa response. Interestingly the mean dyskinesia score during all the duration of the L-Dopa motor effect, the 1 h peak period dyskinesias scores as well as the maximal dyskinesias scores were dose-dependently reduced with both drugs reaching statistical significance at 10 and 30 mg/kg. Our results showed a beneficial antidyskinetic effect of blocking mGluR5 in L-Dopa-treated MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal brain glutamate neurotransmission in PD and decrease dyskinesias.
Morin
Nicolas
N
Molecular Endocrinology and Genomic Research Center, Laval University Medical Center (CHUL), 2705 Laurier Blvd, Quebec (QC), Canada.
Grégoire
Laurent
L
Gomez-Mancilla
Baltazar
B
Gasparini
Fabrizio
F
Di Paolo
Thérèse
T
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine