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The Antiepileptic Drug Levetiracetam Stabilizes the Human Epileptic GABA A Receptors upon Repetitive Activation

2007; Wiley; Volume: 48; Issue: 10 Linguagem: Inglês

10.1111/j.1528-1167.2007.01131.x

1528-1167

Eleonora Palma, Davide Ragozzino, Silvia Di Angelantonio, Addolorata Mascia, Francesca Maiolino, M. Manfredi, Giampaolo Cantore, Vincenzo Esposito, Giancarlo Di Gennaro, P. P. Quarato, Ricardo Miledi, Fabrizio Eusebi,

Lipid Membrane Structure and Behavior

Summary: Purpose: GABA A 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 GABA A receptor run‐down. Methods: GABA A 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 μM LEV. Moreover, the GABA A receptors of pyramidal neurons in human neocortical slices exhibited a current run‐down that was significantly reduced by 1 μM 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 GABA A receptors in the hippocampal subiculum unaltered. These findings point to the GABA A receptor run‐down as an important event in epileptogenesis and as a possible target for testing and screening antiepileptic drugs.