Mode of seizure inhibition by sodium channel blockers, an SV2A ligand, and an AMPA receptor antagonist in a rat amygdala kindling model

Abstract

Purpose: A number of antiepileptic drugs (AEDs) with a variety of modes of action, are effective in treating focal seizures. Several AEDs, such as perampanel (PER), levetiracetam (LEV), lacosamide (LCM), lamotrigine (LTG), and carbamazepine (CBZ), have been shown to elevate the seizure threshold in kindling models. These AEDs are clinically effective, but differences exist in the anti-seizure profiles of drugs with similar modes of action. Therefore, we hypothesized that there are differences in how these AEDs affect seizures. Here, we evaluated the effects of AEDs on various seizure parameters in a rat amygdala kindling model upon stimulation at the after-discharge threshold (ADT) and at three-times the ADT (3xADT) to characterize the differences in the effects of these AEDs.

Methods: PER, LEV, LCM, LTG, CBZ, or vehicle was administered intraperitoneally to fully kindled rats. Changes in Racine seizure score, after-discharge duration (ADD), and latency to Racine score 4 generalized seizure (S₄L) were measured to assess differences in the modes of seizure inhibition among the AEDs. Stimulation at 3xADT was used to eliminate the influence of any AED-induced elevation of the seizure threshold on these parameters.

Results: PER, LEV, LCM, LTG, and CBZ significantly reduced the seizure score from Racine score 5 after stimulation at the ADT; this effect was lost with LEV and LTG after stimulation at 3xADT. PER and LEV significantly shortened the ADD when the seizure focus was stimulated at the ADT, whereas LCM, LTG, and CBZ did not. LEV, LCM, LTG, and CBZ failed to shorten the ADD upon stimulation at 3xADT. PER dose-dependently and significantly increased S₄L, even at doses that were ineffective for seizure score reduction, after stimulation at both the ADT and 3xADT. LEV and LTG significantly increased S₄L after stimulation at the ADT, whereas LCM and CBZ did not significantly increase S₄L at any of the doses tested.

Conclusions: The sodium channel blockers (LCM, LTG, and CBZ) appeared to act by elevation of the seizure threshold via reduction of neuronal excitability, whereas the AMPA receptor antagonist (PER) and the SV2A ligand (LEV), as well as LTG, exerted their effects through the weakening of synaptic transmission in neuronal networks at the seizure focus. Maintenance of the effect of PER even at 3xADT suggests direct and strong modulation of excitatory synaptic transmission by PER, both at the focus and along the seizure propagation route. These findings may provide further rationale for usage of AEDs beyond their respective modes of action.

Keywords: AMPA receptor antagonist; Antiepileptic drug; Focal seizure; Mode of seizure inhibition; Perampanel; Synaptic transmission.