Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys.
Increased glutamatergic activity is believed to play a significant role in the development of levodopa-induced dyskinesias (LID). LID may therefore be attenuated by a reduction in glutamatergic function. This was tested pharmacologically in MPTP monkeys by increasing the formation of kynurenic acid (KYNA), a tryptophan metabolite that inhibits glutamate release and also blocks NMDA receptors directly. KYNA synthesis was stimulated by prolonged systemic administration of the kynurenine 3-hydroxylase inhibitor Ro 61-8048. Four MPTP cynomolgus monkeys received l-dopa (LD; 100mg) with benserazide (25 mg) for one month. Progressively, all these animals developed LID. Four other MPTP monkeys received Ro 61-8048 (50mg/kg) daily 3 h before administration of LD/benserazide for one month. The addition of Ro 61-8048 reduced the development of LID but did not affect the antiparkinsonian efficacy of LD. Moreover, Ro 61-8048 administration caused sustained increases in serum kynurenine and KYNA concentrations, which reverted to basal values 24 h after the last treatment. This effect of Ro 61-8048 was less pronounced in the CSF. These results demonstrate that long-lasting elevation of KYNA levels caused by prolonged inhibition of kynurenine 3-hydroxylase is associated with a significant reduction in LID but does not compromise the benefits of chronic LD therapy.
Grégoire
Laurent
L
Molecular Endocrinology and Oncology Research Center, CHUQ, CHUL Pavillon and Faculty of Pharmacy, Laval University, Québec, PQ, Canada.
Rassoulpour
Arash
A
Guidetti
Paolo
P
Samadi
Pershia
P
Bédard
Paul J
PJ
Izzo
Emanuela
E
Schwarcz
Robert
R
Di Paolo
Thérèse
T
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D007736:Kynurenic Acid / Q000097:blood; D007737:Kynurenine / Q000097:blood; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D013449:Sulfonamides / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use; D013997:Time Factors
D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D007737:Kynurenine; D007980:Levodopa; D050601:Kynurenine 3-Monooxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid