Effects of Valproate, Phenytoin, and MK‐801 in a Novel Model of Epileptogenesis

Abstract

Summary: Purpose:We have developed and characterized a novel model of epileptogenesis based on the convulsive actions of flurothyl in mice. The hallmark feature of this model is a reliable change in the type of seizure expressed in response to flurothyl from generalized clonic to generalized tonic seizures. The purpose of our study was to evaluate the effects of chronic administration of valproate (VPA), phenytoin (PHT), and MK-801 on the change in seizure phenotype observed in our model system.Methods: Male C57BW6J mice received flurothyl seizures on 8 consecutive days. Two hours after the last generalized seizure, chronic drug or vehicle was administered twice daily at 12-h intervals for 28 days. The drugs evaluated were VPA (250 mgkg), PHT (30 mgkg), and MK-801 (0.5 mgkg). After a 7-day drug washout period, mice were retested with flurothyl.Results: Among uninjected or vehicle-injected control mice, there was a significant increase in the proportion of animals expressing tonic seizures after the 28-day stimulation-free interval. Chronic administration of VPA or MK-801, but not PHT, blocked the characteristic change in seizure type from clonic to tonic. Conclusions:The change in seizure phenotype observed after exposure to our paradigm indicates a fundamental reorganization in the propagation of flurothyl-initiated seizures. As in electrical kindling, VPA and MK-801 are effective at blocking or retarding the reorganization, whereas PHT is not. The concordance in pharmacologic profiles between kindling and our model suggests that the processes underlying changes in seizure susceptibility in these two models share mechanisms in common. Key Words: Flurothyl-Generalized seizuresSeizure propagation-Seizure threshold-Epileptogenesis-C57BL/6J mice.A significant body of research indicates that two, largely independent networks in the rodent brain mediate the expression of experimentally induced seizures (1-5). A low-threshold forebrain system mediates expression of generalized clonic seizures, and a highthreshold brainstem system mediates expression of generalized tonic seizures. Propagation of seizure activity in the forebrain system results in the expression of seizures characterized by clonus of the face and forelimbs. By contrast, propagation of seizure activity in the brainstem system results in seizures characterized by tonus in the forelimbs and hindlimbs. Hypothetically, the process of epileptogenesis would involve alterations in the networks responsible for seizure expression. These could involve alterations in the threshold for seizure initiation in either system or alterations in the propagation of seizure activity in either network or between the forebrain or brainstem seizure networks.The process or processes underlying the development of epilepsy are largely unknown, and relatively few animal models are available for investigation of epileptogenic processes. We recently developed an experimental model system in mice that allows detection of a longlasting change in seizure susceptibility and which therefo...

Repeated Generalized Seizures Induce Time-Dependent Changes in the Behavioral Seizure Response Independent of Continued Seizure Induction

“…Thus, within the forebrain seizure system, exposure to our paradigm promotes apparently identical effects to those seen after electrical kindling from the limbic system. In addition, the outcome of a recent pharmacological study from our laboratory indicates that drugs effective at blocking the development of electrical kindling also effectively block the change in seizure phenotype observed after exposure to our model (Applegate et al, 1997). These data indicate that the synaptic mechanisms underlying epileptogenic processes in electrical kindling and our model system share considerable overlap.…”

Bidirectional Transfer Between Electrical and Flurothyl Kindling in Mice: Evidence for Common Processes in Epileptogenesis

“…Flurothyl kindling was conducted according to previously reported studies (17,20,21). In brief, generalized clonic seizures were elicited through infusion (0.15 ml/ min) of a 10% solution of flurothyl dissolved in 95% ethanol on to a gauze pad, suspended at the top of an enclosed chamber.…”

“…On each flurothyl trial, the latency to generalized seizure onset and the final type of seizure expressed were recorded. Seizure responses were evaluated based on a previously described flurothyl seizure-grading system (17,20,21). In brief, after the initial loss of posture, a grade 1-2 flurothyl seizure is used to designate a forebrain or clonic seizure.…”

“…Like electrical kindling, the effects of this flurothyl kindling appear to be permanent (21). One of the characteristic features of this flurothyl model is that after eight flurothyl-induced generalized forebrain (or clonic) seizures (referred to as the induction phase) and a subsequent 28-day stimulation-free interval (the incubation phase), the behavioral seizure phenotype of mice changes from a purely forebrain seizure to a seizure with a more complex phenotype when rechallenged with flurothyl ( 1 7, 20,21). This complex seizure phenotype is manifested as a generalized-onset forebrain seizure that rapidly progresses to a seizure with brainstem (or tonic) manifestations.…”

Antiepileptogenesis and Seizure Prevention Trials with Antiepileptic Drugs: Meta‐Analysis of Controlled Trials

“…In some models, interventions have been performed during the interval to see whether they decrease or delay the onset of spontaneous seizures. Kindling models have been used most for this purpose and suggests that diazepam (DZP), phenobarbital (PB), and valproate (VPA) have antiepileptogenic effects, whereas results are mixed with phenytoin (PHT), and carbamazepine (CBZ) has little or none (10)(11)(12)(13)(14)(15). Although laboratory models can be very helpful in elucidating mechanisms and pointing out drugs that are likely to have an antiepileptogenic effect, one needs to have clinical trials to confirm the effect in humans.…”