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Carbonic Anhydrase Inhibitor Sulthiame Reduces Intracellular pH and Epileptiform Activity of Hippocampal CA3 Neurons
Author(s) -
Leniger Tobias,
Wiemann Martin,
Bingmann Dieter,
Widman Guido,
Hufnagel Andreas,
Bonnet Udo
Publication year - 2002
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1046/j.1528-1157.2002.32601.x
Subject(s) - hippocampal formation , carbonic anhydrase , intracellular , neuroscience , chemistry , pharmacology , biochemistry , enzyme , medicine , biology
Summary: Purpose: Sulthiame is a carbonic anhydrase (CA) inhibitor with an anticonvulsant effect in the treatment of benign and symptomatic focal epilepsy in children. The aim of the study was to elucidate the mode of action of sulthiame with respect to possible changes of intracellular pH (pH i ) that might develop along with sulthiame's anticonvulsant properties. Methods: The effects of sulthiame (a) on pH i of 2′,7‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein‐acetoxymetyl ester (BCECF‐AM) loaded CA3 neurones as well as (b) on epileptiform activity (induced by 50 μ M 4‐aminopyridine) were compared with those of the CA inhibitors acetazolamide and benzolamide. Results: In the majority of neurons, sulthiame (1.0–1.5 m M; n = 8) as well as the membrane permeant acetazolamide (0.5–1.0 m M; n = 6) reversibly decreased pH i by 0.18 ± 0.05 (SD) and 0.17 ± 0.10 (SD) pH units, respectively, within 10 min. The poor membrane permeant benzolamide (1.0–2.0 m M ) had no influence on pH i (n = 8). Sulthiame (1.0–2.5 m M ) and acetazolamide (1.0–2.0 m M ) reversibly reduced the frequency of action potentials and epileptiform bursts after 10–15 min (n = 9, n = 7), whereas benzolamide (1.0–2.0 m M ) had no effect (n = 6). Conclusions: The results suggest that sulthiame acts as a membrane‐permeant CA inhibitor whose beneficial effect on epileptiform activity results at least in part from a modest intracellular acidosis of central neurons.