Abstracts

ANTICONVULSANT PROPERTIES OF BRIVARACETAM ARE NOT MEDIATED BY ITS EFFECTS ON VOLTAGE-GATED SODIUM CHANNELS

Abstract number : 1.204
Submission category : 7. Antiepileptic Drugs
Year : 2013
Submission ID : 1741873
Source : www.aesnet.org
Presentation date : 12/7/2013 12:00:00 AM
Published date : Dec 5, 2013, 06:00 AM

Authors :
I. Niespodziany, V. Andr , N. Lecl re, P. Ghisdal, C. Wolff

Rationale: Brivaracetam (BRV) is a novel antiepileptic drug candidate in Phase III clinical development for the add-on treatment of pharmacoresistant epilepsy. BRV is a high affinity SV2A ligand that shows a 20-fold higher binding affinity than levetiracetam and produces seizure protection in a broad range of preclinical models of epilepsy. A previous study indicated that BRV inhibited voltage-gated sodium current (INa) in primary cortical cultures (Epilepsy Research 2010;88:46) and suggested that this additional mechanism could contribute to the anticonvulsant profile of BRV. To verify the physiological relevance of this potential mode of action we investigated BRV, in comparison with carbamazepine (CBZ), on INa currents expressed in mouse N1E-115 neuroblastoma cells, primary cortical neurons, and adult neurons from sham and pilocarpine-treated animals, and studied the effects of BRV on sustained repetitive firing (SRF).Methods: Using the whole-cell patch-clamp method, the effects of drugs were studied on INa and on SRF, recorded in voltage-clamp and in current-clamp, respectively. Investigations were performed in N1E-115 mouse neuroblastoma cells, in rat primary culture of cortical neurons and in entorhinal cortex (EC) neurons from acute brain slices prepared from sham and pilocarpine-treated adult mice. INa and SRF were recorded from different cells. Drug effects on INa were assessed at the inactivated state of Na+ channels. SRF was evaluated in neurons only, by applying long-lasting depolarization steps every minute from a membrane potential close to the resting membrane potential.Results: In N1E-115 mouse neuroblastoma cells, BRV (100 M) inhibited INa by 30% (40% for CBZ, 100 M) in a state- and use-dependent fashion. In primary cortical neurons, BRV (300 M) produced a weak INa inhibition of 21% (47% for CBZ, 100 M) but did not affect SRF in these neurons in contrast to CBZ (100 M) producing a decrease of 75% of the number of action potential produced during SRF. In EC neurons recorded from acute slices of adult sham or pilocarpine-treated animals BRV (300 M) did not significantly inhibit INa nor did it significantly affect the SRF properties. By contrast, CBZ (100 M) inhibited INa in EC neurons from sham and pilocarpine-treated animals by 20% and 19%, respectively, and reduced the number of action potentials during SRF by 83% and 71% in sham and pilocarpine EC neurons, respectively. We observed no difference in INa voltage-dependent activation and inactivation properties between neurons from sham and pilocarpine-treated animals.Conclusions: BRV produced a small inhibition of Na+ channels in mouse neuroblastoma cells and rat cortical neurons but such effects could not be translated to mature neurons from normal or epileptic mice. BRV, in contrast with CBZ, did not affect SRF in mature neurons. Taken together, these results suggest that the modest impact of BRV on voltage-gated sodium currents is not relevant for its anticonvulsant activity.
Antiepileptic Drugs