STATUS EPILEPTICUS- INDUCED CHANGES IN P-GLYCOPROTEIN EXPRESSION IN THE RAT BRAIN
Abstract number :
2.264
Submission category :
Year :
2002
Submission ID :
55
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Andrey M. Mazarati, Don H. Shin, Ludmila G. Mazarati, Raman Sankar, Claude G. Wasterlain. Neurology, University of California, Los Angeles, Los Angeles, CA; Pediatrics, University of California, Los Angeles, Los Angeles, CA; Research, West Los Angeles VA
RATIONALE: P-glycoprotein (PGP) encoded by multidrug resistance- 1 gene (mdr-1) has been implicated in antiepileptic drug resistance in both epilepsy patients and animal models. We examined whether status epilepticus (SE) results in alterations of PGP immunoreactivity in the rat brain at a time when the standard antiepileptic drug fos-phenytoin (FPHT), which is known to be regulated by PGP, fails to control seizures.
METHODS: SE was induced in adult Wistar rats by either LiCl (3 mEq/kg) and pilocarpine (60 mg/kg) or by 30 min perforant path stimulation through chronically implanted electrodes. PGP immunohistochemistry was examined using anti-mdr-1 polyclonal antibodies (Chemicon) in the coronal sections of paraformaldehyde-fixed brains from the rats euthanized 40 min, 3, 6, 12 and 24 hours after SE induction. FPHT (50 mg/kg) was injected i.v. before, 10 min, 40 min or 3 hours after SE induction.
RESULTS: In naive rats, PGP was confined to capillary endothelial cells diffusely throughout the brain. In both models of SE, PGP staining in the capillaries decreased at 40 min and was undetectable by 6 hours. Simultaneously, PGP- positive astrocytes (identified by GFAP co-labeling) appeared and increased in number, reaching maximal levels at the 12 hr time point. PGP- positive astrocytes were located throughout the brain, including abundant staining in the hippocampus, cortex and thalamus. The effectiveness of a standard dose of FPHT in controlling PPS seizures significantly decreased 40 min hr after SE induction compared to both pre- and early post- treatment. FPHT administration during the third hour of SE failed to affect seizures.
CONCLUSIONS: SE is accompanied by a progressive increase of PGP in astrocytes, which in contrast to the endothelial cell fraction, is known to contribute to the extrusion of xenobiotics from the brain. These changes parallel the failure of FPHT, suggesting that seizure-induced astrocytic PGP expression may contribute to the antiepileptic drug resistance in SE. The reported data are useful for understanding the mechanisms of drug-resistance in epilepsy.
[Supported by: VHA Research Service (CGW), Grant NS 13515 from NINDS (AM, CGW)and DAPA foundation (RS, DS, LM)]