[Expression of multidrug resistance gene and topiramate affect expression of multidrug resistance gene in the hippocampus of spontaneous epileptic rats].
OBJECTIVE
Refractory temporal lobe epilepsy (TCE) shows a unique type of hippocampal damage, referred to as hippocampal sclerosis. The mechanisms underlying drug-refractoriness in TCE are poorly understood, which may be connected with pharmacoresistance to antiepileptic drugs (AEDs). Some studies show that expression of the multidrug resistance gene (mdr1a and mdr1b) and p-glycoprotein encoded by mdr1a and mdr1b are high in the brain, especially in the hippocampus, and the expression may lead to reduction of AEDs concentration in the brain. But most of these studies focused on acute epileptic activity shortly after status epilepticus (SE), spontaneous seizures are seldom studied. The authors used a rat model of kainic acid induced spontaneous seizures to investigate expression of mdr1a and mdr1b mRNA, and explore whether topiramate (TPM) affects expression of mdr1a and mdr1b in the hippocampus.


METHODS
Seizures were induced by intraperitoneal injection of 10 mg/kg kainic acid at postnatal day 28. Control rats were injected with sodium chloride. All rats were divided into 4 groups 1 week after spontaneous seizures developed: status epilepticus complicated with spontaneous seizures (SE, n = 8) group, status epilepticus complicated with spontaneous seizures treated with TPM (SE + TPM, n = 9) group, spontaneous seizures without status epilepticus (N-SE, n = 7) group, spontaneous seizures without status epilepticus treated with TPM (N-SE + TPM, n = 8) group, control (n = 7) group and control treated with TPM (control + TPM, n = 7) group. The treated rats were given therapeutic dose of TPM (25 mg/kg). All the rats were killed on the 42nd day of administration. The mdr1a and mdr1b mRNAs in the hippocampus were measured by RT-PCR.


RESULTS
Expression of mdr1a and mdr1b mRNA in the hippocampus increased significantly in the SE + TPM group, SE group and N-SE + TPM group compared with control group (P < 0.001 or < 0.05). The mRNA in SE + TPM group increased significantly compared with the SE group, too (P < 0.01). The mdr1a and mdr1b mRNA expression in the hippocampus in control + TPM and N-SE groups did not change.


CONCLUSIONS
Frequent seizures, especially status epilepticus resulted in overexpression of mdr1a and mdr1b mRNAs in the hippocampus. The drug-refractoriness mechanism in TCE may be related to overexpression of mdr1a and mdr1b mRNAs. TPM could enhance the expression of mdr1a and mdr1b mRNAs in the hippocampus. Seizure activity and TPM are likely to be the main determinant in enhancing mdr1a and mdr1b mRNA expression in epilepsy.
Jin
Rui-feng
RF
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, China.
Sun
Ruo-peng
RP
Xu
Xiang-ping
XP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D007608:Kainic Acid; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism*; D000077236:Topiramate
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D012333:RNA, Messenger; D000077236:Topiramate; D005632:Fructose; D007608:Kainic Acid