Anticonvulsant efficacy of L-deprenyl (selegiline) during chronic treatment in mice: continuous versus discontinuous administration.
We have previously reported that L-deprenyl (selegiline), an irreversible inhibitor of monoamine oxidase type B (MAO-B), exerts anticonvulsant activity against different seizure types in mice and rats. The anticonvulsant effect of L-deprenyl was rapid in onset but short lasting, arguing in favor of other, reversible mechanisms of L-deprenyl as a basis for the anti-seizure activity. For further evaluation, we administered L-deprenyl continuously via subcutaneously implanted osmotic minipumps in mice and determined the threshold for myoclonic seizures induced by i.v. infusion of pentylenetetrazol repeatedly during prolonged treatment, with treatment periods lasting from 2 to 4 weeks. For comparison with continuous administration via minipumps, L-deprenyl was injected once daily at a dose (10 mg/kg) known to produce complete and irreversible inhibition of MAO-B and anticonvulsant effects after acute administration in rodents. Continuous administration of L-deprenyl, 50 or 100 mg/kg per day, led to a progressive increase in seizure threshold in the absence of any observable adverse effects, while administration of 10 mg/kg per day via minipumps was devoid of any significant anticonvulsant effect. When 10 mg/kg were administered once daily in the afternoon for 4 weeks and the seizure threshold was determined repeatedly in the morning, no significant anticonvulsant effect was observed. The data argue against a critical role of MAO-B inhibition in the anticonvulsant activity of L-deprenyl but suggest that other, reversible biochemical and cellular effects known to occur at higher doses of this drug are involved in this respect. In view of the short half-life of L-deprenyl, these reversible effects can only be maintained during chronic treatment when the drug is given continuously such as via implanted minipumps.
Löscher
W
W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany. wloscher@pharma.tiho-hannover.de
Lehmann
H
H
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D012642:Selegiline / Q000008:administration & dosage* / Q000627:therapeutic use; D013997:Time Factors
D000927:Anticonvulsants; D012642:Selegiline; D010433:Pentylenetetrazole