This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy. In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classical and new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or different mechanisms of action will be discussed.

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Generally, the prevalence of epilepsy does not exceed 0.9% of the population and approximately 70% of epilepsy patients may be adequately controlled with antiepileptic drugs (AEDs). Moreover, status epilepticus (SE) or even a single seizure may produce neurodegeneration within the brain and SE has been recognized as one of acute brain insults leading to acquired epilepsy via the process of epileptogenesis. Two questions thus arise: (1) Are AEDs able to inhibit SE-induced neurodegeneration? and (2) if so, can a probable neuroprotective potential of particular AEDs stop epileptogenesis? An affirmative answer to the second question would practically point to the preventive potential of a given neuroprotective AED following acute brain insults. The available experimental data indicate that diazepam (at low and high doses), gabapentin, pregabalin, topiramate and valproate exhibited potent or moderate neuroprotective effects in diverse models of SE in rats. However, only diazepam (at high doses), gabapentin and pregabalin exerted some protective activity against acquired epilepsy (spontaneous seizures). As regards valproate, its effects on spontaneous seizures were equivocal. With isobolography, some supra-additive combinations of AEDs have been delineated against experimental seizures. One of such combinations, levetiracetam + topiramate proved highly synergistic in two models of seizures and this particular combination significantly inhibited epileptogenesis in rats following status SE. Importantly, no neuroprotection was evident. It may be strikingly concluded that there is no correlation between neuroprotection and antiepileptogenesis. Probably, preclinically verified combinations of AEDs may be considered for an anti-epileptogenic therapy.

Accumulating evidence indicates that amiloride (a potassium-sparing diuretic) exerts the anticonvulsant action in various in vivo and in vitro experiments. Therefore, the objective of this study was to assess the influence of amiloride on the protective action of numerous conventional and second-generation antiepileptic drugs [AEDs: carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), topiramate (TPM), and valproate (VPA)] against maximal electroshock (MES)-induced seizures in mice. Results indicate that amiloride [up to 100 mg/kg, intraperitoneally (i.p.), at 30, 60, and 120 min before the test] neither altered the threshold for electroconvulsions, nor protected the animals against MES-induced seizures in mice. Moreover, amiloride (75 and 100 mg/kg, i.p., 120 min prior to the test) significantly enhanced the anticonvulsant effects of all studied AEDs, except for LTG, by reducing their ED(50) values in the MES test. In contrast, amiloride at 50 mg/kg (i.p.) had no significant effect on the antielectroshock action of the tested AEDs in mice. Estimation of total brain AED concentrations revealed that amiloride (75 mg/kg) significantly increased total brain concentrations of CBZ, OXC, and PB, but not those of LTG, TPM, and VPA in mice. In conclusion, one can ascertain that the potentiation of the antiseizure action of TPM and VPA by amiloride in the MES test and lack of any pharmacokinetic interactions between drugs, make the combinations of amiloride with TPM and VPA of pivotal importance for epileptic patients.