Epilepsia, zyxwvutsrqponm 37(3):269-274, 1996 Lippincott-Raven Publishers, Philadelphia zyxwvutsrqp 0 International League Against Epilepsy zyxwvutsrqpo Chemical Kindling: Implications for Antiepileptic Drugs-Sensitive and Resistant Epilepsy Models Alexei A. Shandra, Andrey M. Mazarati, Leonid S. Godlevsky, and Rooslan S. Vastyanov Department of Normal Physiology, State Medical University, Odessa, Ukraine Summary: The efficacy of phenobarbital (PB) and phe- nytoin (PHT) was evaluated against the convulsions in chemically (picrotoxin,PTX) kindled rats. Two protocols were used: assessment of seizures immediately after the completion of the kindling procedure and after the 2-week postkindling PTX-free period, as compared with acute PTX seizures. Kindled convulsions were more sensitive than acute PTX seizures to the antiepileptic action of PB and PHT. On the other hand, the “postkindling state” was characterized by the enhancement of the seventy of the convulsions in comparison with both kindled and acute PTX seizures and dramatic increase in the resis- tance to the action of antiepileptic drugs (AEDs). It is concluded that the two paradigms-kindling proper and “postkindling”-could be applied as models for AED- sensitive and AED-resistant animal epilepsy models cor- respondingly. Key Words: Chemical kindling-Anti- convulsants-Drug resistance. For animal models to be useful in studies of in- tractable forms of epilepsy, their seizures should not be controlled with standard antiepileptic drugs (AEDs) (1-3). Two conceptual strategies have been used to develop drug-resistant models of epilepsy. The first of these is to use an intense, supramaximal epileptogenic stimulus (4-6). This approach has lit- tle relation to the clinical situation, although finding effective AEDs for such models may disclose basic epileptogenic mechanisms. The other and more promising approach is to develop special strains of animals that are resistant to the action of one or more AEDs (7-9). These models more closely re- semble the human condition in that seizures occur spontaneously, although mechanistically they are of limited value (10) in that they reflect a highly spe- cific genetic mutation that may not be relevant to chronic epilepsy. Kindling is a model of epilepsy that has advan- tages of both the epileptogen-induced and sponta- neous models (4,ll-13). On the one hand, the initi- ation of seizures is definitely the result of epilepto- Received April 5, 1994; revision accepted October 24, 1995. Address correspondence and reprint requests to Professor A. Shandra at Department of Normal Physiology, State Medical University, 2 Valihovsky Lane, 270100 Odessa, Ukraine. Dr. Mazarati’s present address is UCLA, VA Medical Center, Epilepsy Research 11 1N1, 161 11 Plummer St., Sepul- Veda CA 91343, U.S.A. genic manipulation and is tightly time-connected to it. On the other hand, the relation between the be- havioral and electrographic features of seizures and the intensity and duration of the kindling stimuli is very high. Kindling is usually regarded as a drug- resistant model of epilepsy (14). However, “kin- dling” includes at least three processes: seizure de- velopment, occurrence of spontaneous seizures, and a long-lasting increase in seizure susceptibility. Each of these processes probably depends on its own set of basic mechanisms (15). In turn, each process is likely to be differentially sensitive to AEDs. Therefore, the development of seizures (ep- ileptogenesis) responds quite differently to anticon- vulsants than do seizures that have been fully kin- dled (4,16,17). The third process, persistently in- creased seizure susceptibility, which we have termed the “postkindling state” has not yet been studied with regard to the mode of action of AEDs. In these experiments, we studied the action of two AEDs [phenobarbital (PB) and phenytoin (PHT)] on the postkindled state in chemically (pi- crotoxin, PTX) kindled rats and compared the ac- tion with the effects of the two drugs on the kindled convulsions proper. The choice of PTX for inducing acute generalized convulsions also permitted us to compare the drug resistance of two kinds of sei- zures despite the nature of the epileptogenic stimu- lus. 269