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Title: | Brivaracetam does not modulate ionotropic channels activated by glutamate, gamma-aminobutyric acid, and glycine in hippocampal neurons | Authors: | Niespodziany, Isabelle RIGO, Jean-Michel Moonen, Gustave Matagne, Alain Klitgaard, Henrik Wolff, Christian |
Issue Date: | 2017 | Publisher: | WILEY | Source: | EPILEPSIA, 58(11), p. E157-E161 | Abstract: | Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage-clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 mu m, BRV was devoid of any direct effect on currents gated by -aminobutyric acidergic type A, glycine, kainate, N-methyl-D-aspartate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery. | Notes: | [Niespodziany, Isabelle; Matagne, Alain; Klitgaard, Henrik; Wolff, Christian] UCB Pharma, Braine Lalleud, Belgium. [Rigo, Jean-Michel] Hasselt Univ, Biomed Res Inst, Hasselt, Belgium. [Moonen, Gustave] Univ Liege, Sart Tilman Univ Hosp Ctr, Liege, Belgium. | Keywords: | Brivaracetam; GABA; Glycine; NMDA; AMPA; Kainate;brivaracetam; GABA; glycine; NMDA; AMPA; kainate | Document URI: | http://hdl.handle.net/1942/26290 | ISSN: | 0013-9580 | e-ISSN: | 1528-1167 | DOI: | 10.1111/epi.13890 | ISI #: | 000414363000002 | Rights: | © 2017 International League Against Epilepsy | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2018 |
Appears in Collections: | Research publications |
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niespodziany 1.pdf Restricted Access | Published version | 384.47 kB | Adobe PDF | View/Open Request a copy |
BRV ms - revision 2 (1).pdf | Peer-reviewed author version | 589.11 kB | Adobe PDF | View/Open |
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