Diazepam and electrical stimulation of paleocerebellar cortex inhibits seizures in pentylenetetrazol­kindled rats.

The cerebellum is a potent anti­epileptic target for deep brain stimulation in patients with drug­resistant epilepsy. The effects of such stimulation, however, may also favor seizure activity. Our goal was to investigate the effect of cerebellar electrical stimulation (ES) alone and in combination with the anti­epileptic drug diazepam (DIA) on seizure outcome. We used a rat model of pentylenetetrazol kindling, which is characterized by seizures followed by deteriorations in central benzodiazepine­GABAA (BDZ­GABAA) receptors. We tested the effects of ES alone and in combination with DIA (0.1 and 1.0 mg/kg) on seizures. Our data demonstrated: 20 ES trials can prevent the recurrence of clonic­tonic kindled seizures, administration of either DIA­0.1 or ES (5 trials) alone is ineffective on seizures, and combining DIA­0.1 and 5 ES or DIA­1.0 and 5 ES caused an additive effect, prolonged the latency to seizure onset, and prevented recurrence of clonic­tonic seizures. We also observed that ES alone produced either facilitation or inhibition of seizures on EEG. In contrast, the same ES inhibited EEG seizures when delivered after a combination of DIA­1.0 and 5 ES and ultimately prevented the facilitation of the discharges. Lastly, we demonstrated that seizure suppression is intensified when cortical ES is performed after DIA administration. Our data supported the hypothesis that both BDZ­GABAA receptor activity along with cerebellar output comprise the potential mechanisms underlying the peculiar effects of deep brain stimulation in the cerebellum on seizures.

Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice.

PURPOSE: Lacosamide (LCM, Vimpat) is an anticonvulsant with a unique mode of action. This provides lacosamide with the potential to act additively or even synergistically with other antiepileptic drugs (AEDs). The objective of this study was to determine the presence of such interactions by isobolographic analysis. METHODS: The anticonvulsant effect of LCM in combination with other AEDs including carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), and levetiracetam (LEV) at fixed dose ratios of 1:3, 1:1, and 3:1, was evaluated in the 6-Hz-induced seizure model in mice. In addition, the impact of the combinations of LCM with the other AEDs on motor coordination was assessed in the rotarod test. Finally, AED concentrations were measured in blood and brain to evaluate potential pharmacokinetic drug interactions. KEY FINDINGS: All studied AEDs produced dose-dependent anticonvulsant effects against 6-Hz-induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP, or LEV were synergistic. All other LCM/AED combinations displayed additive effects with a tendency toward synergism. Furthermore, no enhanced adverse effects were observed in the rotarod test by combining LCM with other AEDs. No pharmacokinetic interactions were seen on brain AED concentrations. Coadministration of LCM and TPM led to an increase in plasma levels of LCM, whereas the plasma concentration of PHT was increased by coadministration of LCM. SIGNIFICANCE: The synergistic anticonvulsant interaction of LCM with various AEDs, without exacerbation of adverse motor effects, highlights promising properties of LCM as add-on therapy for drug refractory epilepsy.