Abstracts

ENHANCEMENT OF ANTIEPILEPTIC DRUG TREATMENT OF EXPERIMENTAL STATUS EPILEPTICUS THROUGH INHIBITION OF P-GLYCOPROTEIN

Abstract number : 1.309
Submission category :
Year : 2003
Submission ID : 3754
Source : www.aesnet.org
Presentation date : 12/6/2003 12:00:00 AM
Published date : Dec 1, 2003, 06:00 AM

Authors :
Andrey M. Mazarati, Claude G. Wasterlain, Steve Shinmei Neurology, D. Geffen School of Medicine, UCLA, Los Angeles, CA; Research, West LA VA Medical Center, Los Angeles, CA; Brentwood Biomedical Research Institute, Los Angeles, CA

P-glycoprotein (PGP), encoded by a multidrug resistance gene mdr-1, has been implicated in drug resistance in epilepsy. Overexpression of mdr-1 and PGP were reported both in epilepsy patients and animal epilepsy models. Based on our previous findings that the efficacy of several antiepileptic drugs (AEDs) decreased during the course of status epilepticus (SE), we examined whether pharmacological inhibition of PGP improves anticonvulsant treatment of intractable SE.
SE was induced in male Wistar rats by kainic acid (KA, 0.5 [mu]g) injected into the ventral hippocampus. Diazepam (DZP, 10 mg/kg), fos-phenytoin (PHT, 50 mg/kg), or phenobarbital (PHB, 60 mg/kg) was administered i.v. 30 or 90 min after KA. A PGP inhibitor Cyclosporin A (CSA, 75 mg/kg i.p.) was injected 30 min prior to KA in the experiments where AEDs were given after 90 min of seizures. Electrographic activity was recorded for 10 hrs after injection of KA, using AcqKnowledge 3.7 software (Biopac Systems), and analyzed off-line.
SE lasted between 10 and 16 hrs, with the time spent in seizures 4-7 hrs and a number of seizure episodes 250-400. When administered 30 min after KA, all three AEDs stopped SE within 25 min. When injected after 90 min of seizures, all drugs attenuated SE by shortening its duration to 4-6 hrs, total seizure time to 2-3 hrs, and a number of seizures to 105-210 (p[lt]0.05 vs control). CSA alone did not affect SE.
PHT injected 90 min after KA to CSA-treated animals stopped SE within 35 min, with time spent in seizures [le]10 min and seizure count 6-11 (p[lt]0.05 vs CSA-free PHT treatment). In contrast, failure of DZP to treat SE after 90 min of seizures, was not reversed by CSA. Following PHB administration 90 min after KA to CSA-treated animals, both time spent in seizures (0.75-2 hrs) and seizure count (54-110) were significantly lower than in CSA-free PHB group (p[lt]0.05), while SE duration remained unchanged.
Immunohistochemical studies revealed PGP staining in the astrocytes after 90 min of seizures.
During its course, KA-induced SE became resistant to the action of AEDs. Intractable phase of SE correlated with the [italic]de novo[/italic] expression of PGP in the astrocytes. CSA administration restored the effectiveness of PHT during intractable phase of SE, suggesting the involvement of PGP in the resistance to PHT. Resistance to DZP did not depend on PGP, and likely resulted from GABA receptor failure, as it had been shown previously (Kapur et al, 1996). PHB, a PGP-regulated GABAergic agent, showed partial recovery of anticonvulsant efficacy under conditions of CSA treatment, suggesting contribution of both pharmacokinetic and pharmacodynamic components in its failure during intractable phase of SE.
Our data are useful for understanding the mechanisms of drug resistance in epilepsy, and for the development of novel approaches towards the optimization of epilepsy treatment.
[Supported by: Grants NS 43409 and NS 13515 from NIH and VHA Research Service.]