PERIPHERAL AND CENTRAL INHIBITORS OF CATECHOL-O-METHYL TRANSFERASE - EFFECTS ON LIVER AND BRAIN COMT ACTIVITY AND L-DOPA METABOLISM

Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be u seful adjuncts to L-DOPA in the treatment of Parkinson's disease as th ey offer the possibility of increasing the availability of the amino a cid. It is unknown whether a COMT inhibitor which penetrates the blood -brain barrier is preferable to one restricted to extra-cerebral inhib ition. We measured liver and brain COMT activity two hours following a dministration of two COMT inhibitors: entacapone (ENT), mainly periphe rally acting, and dinitrocatechol (DNC), peripheral and central acting . As expected, the full spectrum inhibitor DNC (30mg/kg) induced a nea r total inhibition of liver and brain COMT activity. Unexpectedly, how ever, ENT, at 30mg/kg, produced the same degree of liver and brain COM T inhibition as DNC; using 10mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10-30% inhibition) COMT activity. In a second series of experiments, we admi nistered ENT (2.5, 10, and 30mg/kg) and DNC (30mg/kg) to rats and moni tored extracellular striatal dopamine and dopamine metabolite levels w ith cerebral microdialysis both under basal conditions and following L -DOPA/carbidopa administration. No compound modified basal striatal le vels of dopamine. ENT at 30mg/kg (but not 2.5 or 10mg), as well as DNC , decreased striatal levels of the methylated dopamine metabolite homo vanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated w ith DNC and 30mg/kg ENT (but not 2.5 or 10mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to t he 20% residual liver COMT activity present when the inhibitor was use d at less than full doses. Our data indicate that DNC and ENT both inh ibit striatal HVA formation and increase dopamine formation from exoge nously administered L-DOPA. The dopamine promoting effect of ENT is on ly present, however, at doses which inhibit central as well as periphe ral COMT activity.