Effects of catechol-O-methyltransferase inhibition on the rates of uptake and reversibility of 6-fluoro-L-Dopa trapping in MPTP-induced parkinsonism in monkeys.
The uptake rate constant and the loss rate constant that expresses the reversibility of the uptake process of 6-[18F]fluoro-L-Dopa (FDOPA) were measured by positron emission tomography in the striatum of normal rhesus monkeys and in monkeys with unilateral lesions of the dopaminergic nigro-striatal pathway, induced by intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Each animal was studied twice: with and without pretreatment of the catechol-O-methyltransferase (COMT) inhibitor Ro 40-7592, tolcapone. After pretreatment with tolcapone, there was a very significant increase in plasma FDOPA throughout the course of the study, accompanied by a significant decrease in its main metabolite, 3-O-methylfluorodopa. Tolcapone did not induce a significant change in the uptake rate constant in either the normal or the MPTP-treated striatum. However, after tolcapone pretreatment, there was a significant decrease in the loss rate constant in the MPTP-treated striatum (25%) and a smaller, non-significant decrease in the normal striatum (13%). It is concluded that the COMT inhibitor tolcapone exhibits clear peripheral and central activity. As compared to peripheral COMT inhibitors, this central effect may help preserve and stabilize the synaptic levels of DA and, thus, further improve the effects of L-DOPA therapy in parkinsonian patients.
Doudet
D J
DJ
Department of Medicine, University of British Columbia, Vancouver, Canada. ddoudet@interchange.ubc.ca
Chan
G L
GL
Holden
J E
JE
Morrison
K S
KS
Wyatt
R J
RJ
Ruth
T J
TJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000378:metabolism*; D008253:Macaca mulatta; D009596:Nitrophenols; D010300:Parkinson Disease / Q000378:metabolism*; D000077867:Tolcapone
D001577:Benzophenones; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase