Vol. 288, Issue 3, 984-992, March 1999

Inhibition of Monoamine Oxidase Type A, but Not Type B, Is an Effective Means of Inducing Anticonvulsant Activity in the Kindling Model of Epilepsy¹

Wolfgang Löscher, Holger Lehmann² , Hans-Jürgen Teschendorf, Martin Traut and Gerhard Gross

Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany (W.L., H.L.); and Knoll AG, Central Nervous System Research and Development, Ludwigshafen, Germany (H.-J.T., M.T., G.G.)

The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3,4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3,4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy.