Anticonvulsant action of carbonic anhydrase inhibition.
In this paper we review our data from in vivo and in vitro experiments with mutant, carbonic anhydrase II (CA II) deficient mice (Car2n/Car2n mutants) compared to their nonmutant littermates (Car2n/+ or +/+). In vivo, mutant mice were more resistant to flurothyl-, pentylenetetrazol, and loud sound-induced seizures than normal littermates. The increased resistance to flurothyl seizures was age dependent for clonic seizures, occurring after 19 days of age and disappearing after 90 postnatal days. In in vitro experiments, synaptic transmission in hippocampal slices from mutant mice were more resistant to hypoxia than synaptic transmission in slices from normal littermates. There was almost no difference in hippocampal CA1 long-term potentiation of synaptic transmission between mutants and nonmutants. However, studying in vitro epileptogenesis, we found hippocampal slices from mutants to be more prone to seizures in the low Mg2+ environment than slices from normal littermates. This striking difference between in vivo and in vitro seizures susceptibility in CA II-deficient mutants suggests and existence of an anticonvulsant factor present in conditions in vivo, but not in vitro. We suggest that extracellular proton concentrations (extracellular pH) acting as N-methyl-D-aspartate (NMDA) receptor antagonist may be such a factor. Mutant mice suffer from severe systemic acidosis that can decrease NMDA receptor function and thus be anticonvulsant in vivo. However in vitro, the steady pH of perfusing solution is relatively alkalinic for mutant mouse slices enhancing the thus NMDA receptor conductance and leading to proconvulsant effects. Thus, the anticonvulsant action of CA inhibition in vivo may be mediated by acidotic extracellular pH rather than an accumulation of CO2 as suggested previously.
Velísek
L
L
Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Velísková
J
J
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use*; D004198:Disease Susceptibility; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects
D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors