Effect of Lacosamide on GABA-A evoked currents
Abstract number :
2.034
Submission category :
1. Translational Research: 1B. Models
Year :
2017
Submission ID :
347571
Source :
www.aesnet.org
Presentation date :
12/3/2017 3:07:12 PM
Published date :
Nov 20, 2017, 11:02 AM
Authors :
Gabriele Ruffolo, Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy; Pierangelo Cifelli, Ri.MED Foundation, Palermo, Italy; Cristina Roseti, IRCCS San Raffaele Pisana, Rome, I
Rationale: Lacosamide (LCM) is used as adjunctive treatment for partial-onset seizures. Its mechanism of action is currently matter of discussion even if the drug is mainly known for its effect on the slow inactivation of voltage gated sodium channels even if an interaction of this drug with the CRMP-2 protein has been investigated as possible additional action. Thus, to further clarify LCM mechanism of action, in this study we tested this drug on sodium channels and ligand-gated receptors extracted from human epileptic brain. Methods: To perform our experiments we took advantage of the technique of membrane micro-transplantation in Xenopus oocytes. The electrophysiological recordings were performed on oocytes transplanted with membranes from patients suffering from temporal lobe epilepsy (TLE) and age matched control brain tissue. Results: As first we studied the sodium channel inactivation in tissues from patients suffering from TLE and thus characterized the effect of this drug on a real “human epileptic sodium channel”.Additionally, we wondered if LCM could affect GABAARs or AMPARs function.Interestingly, we did not describe any modification of the AMPAR function following LCM exposure but we found that it can decrease GABAAR desensitization in oocytes injected with TLE tissues. This effect was not reproduced by the inactive stereoisomer S-Lacosamide. Conclusions: Our finding is likely to contribute to explain the mechanism of action of LCM and to explain why it revealed itself a useful tool in the treatment of drug resistant epileptic patients. GABAAR desensitization is in fact a GABAergic impairment that characterizes the phenomenon of drug-resistance and thus drugs able to restore GABAergic function have a prominent role in the pharmacology of epilepsy.Taken together these findings indicate that LCM is indeed able to act via the blockade of sodium channels but that the efficacy of this drug could also be related to the combination of this effect with its action on GABAARs. Funding: This study was funded by UCB pharma (IIS-2014-101617).
Translational Research