Combined effects of epileptic seizure and phenobarbital induced overexpression of P-glycoprotein in brain of chemically kindled rats.
OBJECTIVE
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.


METHODS
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 x kg(-1) x 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.


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
The overexpression of P-glycoprotein in the brain of subjects with pharmacoresistant epilepsy is due to a combination of drug effects and epileptic seizures.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Xinyue
X
Jing
Xiang
X
Liu
Tao
T
Wen
Shanshan
S
Xie
Dan
D
Yao
Xiaodong
X
Liu
Guangji
G
Wang
Lin
L
Xie
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D010433:Pentylenetetrazole / Q000633:toxicity; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000097:blood / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D020112:Rhodamine 123; D010433:Pentylenetetrazole; D010634:Phenobarbital