The antiepileptic drug levetiracetam stabilizes the human epileptic GABAA receptors upon repetitive activation.
OBJECTIVE
GABAA receptors from the brain of patients afflicted with mesial temporal lobe epilepsy (MTLE) become less efficient (run-down) when repetitively activated by GABA. Experiments were designed to investigate whether the antiepileptic drug, levetiracetam (LEV), which is used as an adjunctive treatment for medically intractable MTLE, counteracts the GABAA receptor run-down.


METHODS
GABAA receptors were microtransplanted from the brains of patients afflicted with MTLE into Xenopus oocytes. The GABA-current run-down, caused by repetitive applications of GABA, was investigated using the standard two-microelectrode voltage-clamp technique. Additionally, the GABA-current run-down was investigated directly on pyramidal neurons in human MTLE cortical slices.


RESULTS
It was found that, in oocytes injected with membranes isolated from the MTLE neocortex, the GABA-current run-down was inhibited by a 3-h pretreatment with 0.5-100 microM LEV. Moreover, the GABAA receptors of pyramidal neurons in human neocortical slices exhibited a current run-down that was significantly reduced by 1 microM LEV. Interestingly, the run-down in oocytes injected with membranes isolated from the MTLE hippocampal subiculum was not affected by LEV.


CONCLUSIONS
We report that the antiepileptic LEV strengthens GABA inhibition of neuronal circuits by blocking the receptor run-down in the cortex whilst leaving the run-down of GABAA receptors in the hippocampal subiculum unaltered. These findings point to the GABAA receptor run-down as an important event in epileptogenesis and as a possible target for testing and screening antiepileptic drugs.
Palma
Eleonora
E
Dipartimento di Fisiologia Umana e Farmacologia, Universita' di Roma La Sapienza, Roma, Italy. eleonora.palma@uniroma1.it
Ragozzino
Davide
D
Di Angelantonio
Silvia
S
Mascia
Addolorata
A
Maiolino
Francesca
F
Manfredi
Mario
M
Cantore
Giampaolo
G
Esposito
Vincenzo
V
Di Gennaro
Giancarlo
G
Quarato
Pierpaolo
P
Miledi
Ricardo
R
Eusebi
Fabrizio
F
D000328:Adult; D000368:Aged; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D016380:Brain Tissue Transplantation / Q000502:physiology; D002462:Cell Membrane / Q000637:transplantation; D002648:Child; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008839:Microelectrodes; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014981:Xenopus; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology
D000927:Anticonvulsants; D011963:Receptors, GABA-A; D000077287:Levetiracetam; D005680:gamma-Aminobutyric Acid; D010889:Piracetam