INHIBITION OF TYPE-A AND TYPE-B MONOAMINE-OXIDASE BY 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (3) , 696-701
Abstract
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied as an inhibitor of type A monoamine oxidase (MAO) acting on [14C]serotonin as substrate and of type B MAO acting on [14C]phenylethylamine as substrate. MPTP was a reasonably potent (Ki = 9 .mu.M), competitive, reversible inhibitor of MAO-A from rat brain in vitro. MPTP given at a 30 mg/kg i.p. dose antagonized the irreversible inactivation of MAO-A in rat brain by pargyline, indicating that it inhibited MAO-A in vivo. At that same dose, MPTP prevented the conversion of dopamine released by Ro 4-1284 [2-ethyl-2,3,4,6,7,11b-hexa-hydro-3-isobutyl-9,10-dimethoxy-2H-benzo[a]-quinolizin-2-ol HCl] to 3,4-dihydroxyphenylacetic acid and attenuated its conversion to homovanillic acid. Because dopamine is mainly deaminated by MAO-A, at least in rodent brain, inhibition of MAO-A by MPTP might play some part in its production of persistent effects on striatal dopamine neurons such as protection of intraneuronal, extragranular dopamine from deamination. MPTP was less potent as an inhibitor by MAO-B from rat brain in vitro (Ki = 106 .mu.M). In contrast to the inhibition of MAO-A, the inhibition of MAO-B by MPTP showed noncompetitive kinetics, was not fully reversible by dialysis and was time dependent. The characteristics of MAO-B inhibition are like those of a kcat inhibitor, which is acted upon by an enzyme to produce a reactive product that can covalently attach to the enzyme or other macromolecules. Although little inactivation of MAO-B was found in rat brain in vivo after MPTP injection, the possibility that a product or products of MAO-B action on MPTP may contribute to the persistent effects of MPTP on striatal dopamine neurons suggests a 2nd way in which interaction between MPTP and MAO might be important in the in vivo actions of MPTP. Because MPTP apparently causes irreversible Parkinson''s disease in humans and a Parkinsonian-like syndrome in monkeys associated with neurotoxic effects on striatal dopamine neurons, a more complete understanding of its actions on dopamine neurons is urgently needed. Interactions of MPTP with MAO-A and with MAO-B can be considered as such research progresses.

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