Abstract
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.
Highlights
Bromides started pharmacotherapy of epilepsy more than 150 years ago but their therapeutic index was quite low [1,2]
In 1912, phenobarbital was introduced as an effective antiepileptic drug (AED) and it is the only antiepileptic whose discovery was not associated with animal seizure tests
AEDs clearly represent a symptomatic approach in the treatment of epilepsy, reducing the frequency and severity of seizures [66]
Summary
Bromides started pharmacotherapy of epilepsy more than 150 years ago but their therapeutic index was quite low [1,2]. AEDs share multiple mechanisms of action (topiramate, valproate and others) or exert just one mechanism, for instance tiagabine or vigabatrin. Benzodiazepines, carbamazepine, ethosuximide, phenobarbital, phenytoin and valproate belong to conventional (or the first generation) antiepileptics whilst gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate or vigabatrin may be examples of the second generation. The first mechanism is shared by carbamazepine, eslicarbazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin and phenytoin. GABA-mediated inhibition is enhanced by benzodiazepines, phenobarbital, topiramate, tiagabine, valproate and vigabatrin whilst inhibition of glutamate-mediated excitation is mediated by lamotrigine, perampanel and topiramate [2,3,4]. English language articles were considered in PUBMED databases and the search areas included: mechanisms of action of AEDs, mechanisms of epileptogenesis, AEDs and epileptogenesis, inhibition of epileptogenesis by non-AEDs and other agents and clinical data on inhibition of epileptogenesis. A limited number of important earlier publications was considered
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