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Combined effects of epileptic seizure and phenobarbital induced overexpression of P‐glycoprotein in brain of chemically kindled rats
Author(s) -
Jing Xinyue,
Liu Xiang,
Wen Tao,
Xie Shanshan,
Yao Dan,
Liu Xiaodong,
Wang Guangji,
Xie Lin
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00634.x
Subject(s) - phenobarbital , p glycoprotein , epilepsy , endocrinology , hippocampus , medicine , western blot , chemistry , pharmacology , anticonvulsant , biochemistry , multiple drug resistance , psychiatry , gene , antibiotics
Background and purpose: The multidrug resistance of epilepsy may result from the overexpression of P‐glycoprotein, but the mechanisms are unclear. We investigated whether the overexpression of P‐glycoprotein in the brains of subjects with pharmacoresistant epilepsy resulted from both drug effects and seizure activity. Experimental approach: Kindled rats were developed by injecting a subconvulsive dose of pentylenetetrazole (33 mg·kg −1 ·day −1 , i.p.) for 28 days. Groups were then treated with an oral dose of phenobarbital (45 mg·kg −1 ·day −1 ) for 40 days. In accord with behavioural observations, P‐glycoprotein activity in brain was assessed using brain‐to‐plasma concentration ratios of rhodamine 123. P‐glycoprotein levels in the brain regions were further evaluated using RT‐PCR and Western blot analysis. The distribution of phenobarbital in the brain was assessed by measuring phenobarbital concentrations 1 h following its oral administration. Key results: The kindling significantly increased P‐glycoprotein activity and expression. Good associations were found among P‐glycoprotein activity, expression and phenobarbital concentration in the hippocampus. Short‐term treatment with phenobarbital showed good anti‐epileptic effect; the maximum effect occurred on day 14 when overexpression of P‐glycoprotein was reversed. Continuous treatment with phenobarbital had a gradually reduced anti‐epileptic effect and on day 40, phenobarbital exhibited no anti‐epileptic effect; this was accompanied by both a re‐enhancement of P‐glycoprotein expression and decreased phenobarbital concentration in the hippocampus. P‐glycoprotein function and expression were also increased in age‐matched normal rats treated with phenobarbital. Conclusions and implications: The overexpression of P‐glycoprotein in the brain of subjects with pharmacoresistant epilepsy is due to a combination of drug effects and epileptic seizures.