Improved Therapy of Parkinson's Disease with Tolcapone, a Central and Peripheral COMT Inhibitor with an S-Adenosyl-L-Methionine-Sparing Effect

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Tolcapone (Ro 40-7592) is a novel catechol-O-methyltransferase (COMT) inhibitor active both in extracerebral tissues and in the central nervous system (CNS). Only minor amounts of tolcapone are O-methylated and converted into the inactive metabolite Ro 40-7591. The two oxidated metabolites of tolcapone, Ro 47-1868 and Ro 47-1669, are present in low concentrations in human plasma and exert COMT-inhibitory effects similar to that of the parent compound. In contrast to entacapone, which does not pass the blood-brain barrier, tolcapone produces marked COMT inhibition in the CNS, with concomitant decrease of homovanillic acid (HVA) and an increase of striatal S-adenosyl-L-methionine (SAM) concentrations. SAM is the methyl donor used by COMT in the O-methylation of levodopa, dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC). Blockade of O-methylation of levodopa and DA by tolcapone also reduces the consumption of SAM, thus increasing the availability of levodopa and DA by concomitantly maintaining, unchanged in the CNS, the endogenous level of the methyl donor and that of its demeth-ylated product S-adenosylhomocysteine (SAH). Tolcapone dose-dependently increases the content of SAM in rat striatum. A high dose of tolcapone (30 mg/kg p.o.), which induces a pronounced COMT inhibition in red blood cells (RBCs), also elevates striatal levels of SAM for several hours. Our results show that the inhibition of COMT in RBCs can be used as an easily accessible peripheral marker for monitoring brain COMT inhibition. Moreover, our results support the concept that in the therapy of Parkinson's disease (PD), coadministration of Madopar or Sinemet with tolcapone will improve the beneficial effect of levodopa by increasing its bioavailability to the CNS. Tolcapone does not appear to interfere with SAM-dependent transmethylation enzymes other than COMT. The central and peripheral COMT inhibition induced by tolcapone, together with the reduced utilization of SAM, should improve the therapy of PD and PD-associated affective disorders. Moreover, tolcapone, by increasing the level of SAM in the CNS may in itself produce antidepressant effects by facilitating transmethylation reactions.

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