Reference : The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric ...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/5028
The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents
English
Rigo, Jean-Michel [Universiteit Hasselt - UH > > > >]
Hans, Grégory mailto [Centre Hospitalier Universitaire de Liège - CHU > > Anesthésie et réanimation >]
Nguyen, Laurent mailto [Université de Liège - ULg > Département des sciences cliniques > Neurologie >]
Rocher, Véronique [> > > >]
Belachew, Shibeshih mailto [Université de Liège - ULg > Département des sciences cliniques > Neurologie >]
Malgrange, Brigitte mailto [Université de Liège - ULg > > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc. >]
Leprince, Pierre mailto [Université de Liège - ULg > > CNCM/ Centre fac. de rech. en neurobiologie cell. et moléc. >]
Moonen, Gustave mailto [Université de Liège - ULg > Département des sciences cliniques > Neurologie - Doyen de la Faculté de Médecine]
Selak, Ivan [Centre Hospitalier Universitaire de Liège - CHU > > Neurologie Sart Tilman >]
Matagne, Alain [ > > ]
Klitgaard, Henrik [UCB Pharma > > > >]
Jul-2002
British Journal of Pharmacology
Nature Publishing Group
136
5
659-672
Yes (verified by ORBi)
International
0007-1188
London
[en] GABA(A) receptor ; glycine receptor ; levetiracetam ; beta-carbolines ; zinc ; anti-epileptic drugs ; inhibition reversal ; whole-cell patch-clamp ; sound-susceptible mice
[en] 1 In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra(R)) may involve modulation of inhibitory neurotransmission. 2 GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The effect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct effect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct effects contrasted with a potent ability of LEV (EC50 = 1-10 muM) to reverse the inhibitory effects of the negative allosteric modulators zinc and beta-carbolines on both GABA(A) and glycine receptor-mediated responses. 5 Clonazepam, phenobarbital and valproate showed a similar ability to reverse the inhibition of beta-carbolines on GABA-gated currents. Blockade of zinc inhibition of GABA responses was observed with clonazepam and ethosuximide. Phenytoin was the only AED together with LEV that inhibited the antagonism of zinc on glycine-gated currents and only clonazepam and phenobarbital inhibited the action of DMCM. 6 LEV (17 mg kg(-1)) produced a potent suppression of sound-induced clonic convulsions in mice. This protective effect was significantly abolished by co-administration of the beta-carboline FG 7142, from a dose of 5 mg kg(-1). In contrast, the benzodiazepine receptor antagonist flumazenil (up to 10 mg kg(-1)) was without any effect on the protection afforded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the anti-epileptic mechanism(s) of action of LEV.
Fonds de la Recherche Scientifique (Communauté française de Belgique) - F.R.S.-FNRS ; Fondation Médicale Reine Elisabeth
Researchers ; Professionals ; Students
http://hdl.handle.net/2268/5028
10.1038/sj.bjp.0704766

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