Norfluoxetine and fluoxetine have similar anticonvulsant and Ca2+ channel blocking potencies.
Norfluoxetine is the most important active metabolite of the widely used antidepressant fluoxetine but little is known about its pharmacological actions. In this study the anticonvulsant actions of norfluoxetine and fluoxetine were studied and compared to those of phenytoin and clonazepam in pentylenetetrazol-induced mouse epilepsy models. Pretreatment with fluoxetine or norfluoxetine (20mg/kg s.c.), as well as phenytoin (30 mg/kg s.c.) and clonazepam (0.1mg/kg s.c.) significantly increased both the rate and duration of survival, demonstrating a significant protective effect against pentylenetetrazol-induced epilepsy. These effects of norfluoxetine were similar to those of fluoxetine. According to the calculated combined protection scores, both norfluoxetine and fluoxetine were effective from the concentration of 10mg/kg, while the highest protective action was observed with clonazepam. Effects of norfluoxetine and fluoxetine on voltage-gated Ca2+ channels were evaluated by measuring peak Ba2+ current flowing through the Ca2+ channels upon depolarization using whole cell voltage clamp in enzymatically isolated rat cochlear neurons. The current was reduced equally in a concentration-dependent manner by norfluoxetine (EC50=20.4+/-2.7 microM, Hill coefficient=0.86+/-0.1) and fluoxetine (EC50=22.3+/-3.6 microM, Hill coefficient=0.87+/-0.1). It was concluded that the efficacy of the two compounds in neuronal tissues was equal, either in preventing seizure activity or in blocking the neuronal Ca2+ channels.
Kecskeméti
Valéria
V
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Faculty of Medicine, H-1445 Budapest, P.O. Box 370, Nagyvárad tér 4, Hungary. kecsval@pharma.sote.hu
Rusznák
Zoltán
Z
Riba
Pál
P
Pál
Balázs
B
Wagner
Róbert
R
Harasztosi
Csaba
C
Nánási
Péter P
PP
Szûcs
Géza
G
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001464:Barium / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002998:Clonazepam / Q000494:pharmacology; D017626:Cochlear Nucleus / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D000927:Anticonvulsants; D001464:Barium; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002998:Clonazepam; D005473:Fluoxetine; D010672:Phenytoin; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine