Abstracts

Effects of the antiepileptic drug lacosamide on firing properties and sodium currents in dentate gyrus granule cells of epileptic animals

Abstract number : 3.245
Submission category : 7. Antiepileptic Drugs
Year : 2015
Submission ID : 2322939
Source : www.aesnet.org
Presentation date : 12/7/2015 12:00:00 AM
Published date : Nov 13, 2015, 12:43 PM

Authors :
D. Holtkamp, T. Opitz, I. Niespodziany, C. Wolff, H. Beck

Rationale: Up to 30% of chronic epilepsy patients remain refractory to antiepileptic drugs (AEDs). In the case of conventional sodium channel-acting AEDs, a loss of use-dependent block of sodium channels both in human and experimental epilepsy has been demonstrated as a potential underlying mechanism of pharmacoresistance. Lacosamide (LCM) is approved as monotherapy or adjunctive therapy in adults with partial-onset seizures (POS) in the US, and as adjunctive therapy in adults with POS in the EU and several other countries and we have asked if this new antiepileptic drug overcomes this resistance mechanism. We thought this likely because LCM selectively enhances slow inactivation of voltage-gated fast transient sodium currents without affecting the fast inactivation properties, differentiating it from many other sodium channel blocking AEDs.Methods: We have used patch-clamp recordings in granule cells from hippocampal slices to assess if LCM inhibits differently repetitive firing evoked by current injection (8 sec) in control vs. chronically epileptic rats (pilocarpine model of epilepsy). Voltage-clamp recordings were performed in isolated granule cells to assess the underlying effects on voltage-gated sodium channels.Results: LCM (30-300 µM) induced a reversible and dose-dependent block of action potential firing in neurons from control and pilocarpine treated animals. The block of action potential firing was use-dependent, increasing with more prolonged current injections. Interestingly, LCM did not show loss of efficacy in neurons from pilocarpine-treated rats. In contrast, the onset of the blocking effects on firing rates was even faster in pilocarpine-treated rats. We then assessed the effects of LCM on sodium channel properties in isolated granule cells from control and epileptic animals. No significant effect of 100 µM LCM could be observed on sodium channel voltage-dependent activation and fast inactivation. Likewise, the development and the recovery of sodium channel slow inactivation were similar in control and epileptic animals, and unaltered by LCM. A careful examination of action potential initiation indicated that LCM may affect axon initial segment sodium channels during repetitive firing in a use-dependent manner.Conclusions: These results show that LCM maintains activity in experimental epilepsy and that it’s mechanism of inhibition may rely on slow, use-dependent inhibition of axon initial segment sodium channels. UCB Pharma-sponsored
Antiepileptic Drugs