Reduction of voltage-operated potassium currents by levetiracetam: a novel antiepileptic mechanism of action?
Levetiracetam (ucb L059; Keppra) is a novel antiepileptic drug. Its effects on action potential generation and voltage-operated potassium currents were studied in acutely isolated hippocampal CA1 neurones from rat and guinea pig, using the patch-clamp technique in the whole-cell configuration. (i) Levetiracetam reduced repetitive action potential generation and affected the single action potential. Levetiracetam, 100 microM, decreased the total number of action potentials and reduced the total depolarisation area of repetitive action potentials by 21%. Furthermore, levetiracetam increased the duration of the first action potential slightly, prolonged that of the second action potential by 13% and decreased the slope of rise by 23%. (ii) Levetiracetam decreased the voltage-operated potassium current. Without effect on sodium and A-type potassium currents, levetiracetam, 100 microM, reduced the delayed rectifier current by 26%. The concentration of half-maximal block was 47 microM for guinea pig and 6 microM for rat neurones. Thus, the reduction of repetitive action potential generation by levetiracetam can be attributed, unexpectedly, to a moderate reduction of the delayed rectifier potassium current, as supported by a simulation of action potential generation. This suggests that a reduction of potassium currents may contribute to the antiepileptic effect(s) of levetiracetam.
Madeja
Michael
M
Institute for Physiology, University Münster, Robert-Koch-Str. 27A, 48149 Münster, Germany. madejam@ghst.de
Margineanu
Doru Georg
DG
Gorji
Ali
A
Siep
Elke
E
Boerrigter
Paul
P
Klitgaard
Henrik
H
Speckmann
Erwin-Josef
EJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D006168:Guinea Pigs; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D000077287:Levetiracetam; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000295:instrumentation / Q000379:methods; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D000927:Anticonvulsants; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D000077287:Levetiracetam; D019789:Tetraethylammonium; D015761:4-Aminopyridine; D010889:Piracetam