title: Topiramate modulates pH of hippocampal CA3 neurons by combined effects on carbonic anhydrase and Cl-/HCO3- exchange.
abstract: Topiramate (TPM) is an anticonvulsant whose impact on firing activity and intracellular pH (pHi) regulation of CA3 neurons was investigated. Using the 4-aminopyridine-treated hippocampal slice model bathed in bicarbonate-buffered solution, TPM (25-50 microm) reduced the frequency of epileptiform bursts and action potentials without affecting membrane potential or input resistance. Inhibitory effects of TPM were reversed by trimethylamine-induced alkalinization. TPM also lowered the steady-state pHi of BCECF-AM-loaded neuronal somata by 0.18+/-0.07 pH units in CO(2)/HCO(3)(-)-buffered solution. Subsequent to an ammonium prepulse, TPM reduced the acidotic peak but clearly slowed pHi recovery. These complex changes were mimicked by the protein phosphatase inhibitor okadaic acid. Alkalosis upon withdrawal of extracellular Cl(-) was augmented by TPM. Furthermore, at decreased pHi due to the absence of extracellular Na(+), TPM reversibly increased pHi. These findings demonstrate that TPM modulates Na(+)-independent Cl(-)/HCO(3)(-) exchange. In the nominal absence of extracellular CO(2)/HCO(3)(-) buffer, both steady-state pHi and firing of epileptiform bursts remained unchanged upon adding TPM. However, pHi recovery subsequent to an ammonium prepulse was slightly increased, as was the case in the presence of the carbonic anhydrase (CA) inhibitor acetazolamide. Thus, a slight reduction of intracellular buffer capacity by TPM may be due to an inhibitory effect on intracellular CA. Together, these findings show that TPM lowers neuronal pHi most likely due to a combined effect on Na(+)-independent Cl(-)/HCO(3)(-) exchange and CA. The apparent decrease of steady-state pHi may contribute to the anticonvulsive property of TPM.
authors.affiliation: Department of Neurology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany. tobias.leniger@uni-essen.de
authors.forename: Tobias
authors.initials: T
authors.lastname: Leniger
authors.forename: Jan
authors.initials: J
authors.lastname: Thöne
authors.forename: Martin
authors.initials: M
authors.lastname: Wiemann
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D012964:Sodium / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D001639:Bicarbonates; D002257:Carbonic Anhydrase Inhibitors; D027963:Chloride-Bicarbonate Antiporters; D002712:Chlorides; D004791:Enzyme Inhibitors; D017923:Sodium-Hydrogen Exchangers; D000643:Ammonium Chloride; D000077236:Topiramate; D002245:Carbon Dioxide; D019319:Okadaic Acid; D005632:Fructose; D012964:Sodium; D010744:Phosphoric Monoester Hydrolases; D002256:Carbonic Anhydrases