The effect of losigamone (AO-33) on electrical activity and excitatory amino acid release in mouse cortical slices.
1. Losigamone is a novel anticonvulsant the mechanism of action of which is not known. This study investigated the effect of losigamone on spontaneous, NMDA- and AMPA-induced depolarizations in the cortical wedge preparation of the DBA/2 mouse (which are susceptible to sound-induced seizures) and on endogenous amino acid release from BALB/c mouse cortical slices. 2. Cortical wedges exhibit spontaneous depolarizations in magnesium-free medium and losigamone was effective in significantly reducing these spontaneous depolarizations at concentrations of 100 microM and above. 3. NMDA-induced depolarizations were significantly reduced by losigamone at concentrations of 25 microM and above. Losigamone had no effect on AMPA-induced depolarizations. 4. Veratridine (20 microM) and potassium (60 mM) were used to stimulate the release of amino acids from mouse cortex. Veratridine-stimulated release of glutamate was significantly reduced by losigamone at concentrations of 100 microM and above, while potassium-stimulated release was significantly reduced by losigamone at 200 microM. 5. NMDA antagonism and inhibition of excitatory amino acid release may contribute to the anticonvulsant effect of losigamone.
Srinivasan
J
J
Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Heath Park, Cardiff.
Richens
A
A
Davies
J A
JA
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000378:metabolism*; D005663:Furans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016202:N-Methylaspartate / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018846:Excitatory Amino Acids; D005663:Furans; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C065427:losigame