IMPROVED THERAPY OF PARKINSONS-DISEASE WITH TOLCAPONE, A CENTRAL AND PERIPHERAL COMT INHIBITOR WITH AN S-ADENOSYL-L-METHIONINE-SPARING EFFECT

Tolcapone (Ro 40-7592) is a novel catechol-O-methyltransferase (COMT) inhibitor active both in extracerebral tissues and in the central nerv ous system (CNS). Only minor amounts of tolcapone are O-methylated and converted into the inactive metabolite Ro 40-7591. The two oxidated m etabolites of tolcapone, Ro 47-1868 and Ro 47-1669, are present in low concentrations in human plasma and exert COMT-inhibitory effects simi lar to that of the parent compound. In contrast to entacapone, which d oes not pass the blood-brain barrier, tolcapone produces marked COMT i nhibition in the CNS, with concomitant decrease of homovanillic acid ( HVA) and an increase of striatal S-adenosyl-L-methionine (SAM) concent rations. SAM is the methyl donor used by COMT in the O-methylation of levodopa, dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC). B lockade of O-methylation of levodopa and DA by tolcapone also reduces the consumption of SAM, thus increasing the availability of levodopa a nd DA by concomitantly maintaining, unchanged in the CNS, the endogeno us level of the methyl donor and that of its demethylated product S-ad enosylhomocysteine (SAH). Tolcapone dose-dependently increases the con tent 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 s how that the inhibition of COMT in RBCs can be used as an easily acces sible peripheral marker for monitoring brain COMT inhibition. Moreover , our results support the concept that in the therapy of Parkinson's d isease (PD), coadministration of Madopar or Sinemet with tolcapone wil l improve the beneficial effect of levodopa by increasing its bioavail ability to the CNS. Tolcapone does not appear to interfere with SAM-de pendent transmethylation enzymes other than COMT. The central and peri pheral COMT inhibition induced by tolcapone, together with the reduced utilization of SAM, should improve the therapy of PD and PD-associate d affective disorders. Moreover, tolcapone, by increasing the level of SAM in the CNS may in itself produce antidepressant effects by facili tating transmethylation reactions.