Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys.
Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa-induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3-hydroxylase inhibitor Ro 61-8048, which raises KYNA levels acutely. Ro 61-8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose-dependently after Ro 61-8048 administration, alone or in combination with levodopa. Coadministration of Ro 61-8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease.
Samadi
Pershia
P
Centre de Recherche en Neurosciences, Centre Hospitalier Universitaire de Québec, Québec, Canada.
Grégoire
Laurent
L
Rassoulpour
Arash
A
Guidetti
Paolo
P
Izzo
Emanuela
E
Schwarcz
Robert
R
Bédard
Paul J
PJ
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D007736:Kynurenic Acid / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase; D007980:Levodopa / Q000627:therapeutic use*; D008252:Macaca fascicularis; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D013449:Sulfonamides / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013844:Thiazoles / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D013997:Time Factors
D000978:Antiparkinson Agents; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D007980:Levodopa; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid