Levetiracetam inhibits Na+-dependent Cl-/HCO3- exchange of adult hippocampal CA3 neurons from guinea-pigs.
The novel anticonvulsant levetiracetam (LEV) was tested for effects on bioelectric activity and intracellular pH (pHi) regulation of hippocampal CA3 neurons from adult guinea-pigs. In 4-aminopyridine-treated slices, LEV (10-100 microm) reduced the frequency of action potentials and epileptiform bursts of CA3 neurons by 30-55%, while the shape of these potentials remained largely unchanged. Suppressive effects were reversed by an increase of pHi with trimethylamine (TMA). Using BCECF-AM-loaded slices, we found that LEV (10-50 microm) reversibly lowered neuronal steady-state pHi by 0.19 +/- 0.07 pH units in the presence of extracellular CO2/HCO3- buffer. In the nominal absence of extracellular CO2/HCO3- or in Na+-free CO2/HCO3(-)-buffered solution, LEV had no effect on steady-state pHi. Recovery of pHi subsequent to ammonium prepulses remained unchanged in the absence of CO2/HCO3- buffer, but was significantly reduced by LEV in the presence of CO2/HCO3- buffer. These findings show that LEV inhibits HCO3(-)-dependent acid extrusion, but has no effect on Na+/H+ exchange. LEV did not affect Na+-independent Cl-/HCO3- exchange because intracellular alkalosis upon withdrawal of extracellular Cl- remained unchanged. These data show that LEV at clinically relevant concentrations inhibits Na+-dependent Cl-/HCO3- exchange, lowers neuronal pHi, and thereby may contribute to its anticonvulsive activity.
Leniger
Tobias
T
Department of Neurology, University of Essen, Hufelandstr. 55, Essen 45122, Germany. tobias.leniger@uni-essen.de
Thöne
Jan
J
Bonnet
Udo
U
Hufnagel
Andreas
A
Bingmann
Dieter
D
Wiemann
Martin
M
D000200:Action Potentials; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002021:Buffers; D002414:Cations, Monovalent; D027963:Chloride-Bicarbonate Antiporters / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D000077287:Levetiracetam; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D013997:Time Factors
D000927:Anticonvulsants; D002021:Buffers; D002414:Cations, Monovalent; D027963:Chloride-Bicarbonate Antiporters; D000077287:Levetiracetam; D012964:Sodium; D010889:Piracetam