Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 186, Issue 2, Pages 161-167Publisher
ELSEVIER
DOI: 10.1016/j.bbr.2007.08.007
Keywords
dyskinesia; kynurenic acid; kynurenine; L-dopa; MPTP; Parkinson's disease
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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; 100 mg) with benserazide (25 mg) for one month. Progressively, all these animals developed LID. Four other MPTP monkeys received Ro 61-8048 (50 mg/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. (C) 2007 Elsevier B.V. All rights reserved.
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