Levetiracetam And Flunarizine Affect Expression Of Multidrug Resistance Gene

Background One-third of patients with epilepsy suffer from intractable seizures, which cannot be properly controlled with the current pharmacotherapy.Levetiractam is a new and effective antiepileptic drug,and there is little knowledge about it's effect on the expression of mdr.So we have make a rat model of spontaneous seizures using kainic acid to study influence of levetiractam to mdr.On the other hand,Flunarizine is a kind of Ca²⁺antagon and some studies show that it can reverse the expression of mdr in rats.But if it can use in the treatment of infractory epilepsy in pediatrics and what is the mechanism of action is still not very clear.Objective We investigated express of mdr1a and mdr1b mRNA and studied whether levetiractam(LEV)affects the expression of mdr1a and mdr1b in the hippocampus of spontaneous seizures rat.To explore the effect and tolerance of flunarizine,which used as an add-on treatment for drug-resistent epilepsy in pediatrics.Methods Spontaneous recurrent seizure were induced by intraperitoneal injection of 1mg/kg kainic acid at postnatal day 7.Control rats were injected with sodium chloride.Then all rats were classified as 4 groups after spontaneous seizures developed: spontaneous seizures(EP,n=13)group,spontaneous seizures treated with LEV (EP+LEV,n=15)group,control(n=16)group and control treated with LEV(control +LEV,n=16)group.The treated rats were given dose of LEV(80mg/kg),dissolving in 0.9%Sodium Chloride for 10mg/mL,twice a day.All rat were killed at the 56th day of intragastric administration and separate the hippocampus to weigh.The expression of mdr1a and mdr1b mRNA in the hippocampus were measured by RT-PCR.Furthermore,the expression of mdr in peripheral blood of 86 subjects were also tested by PT-PCR.All subjects were divided into intractable epilepsy(64)group and control(22)group,and the intractable epilepsy was made up of flunarizine treatmet (36)and placebo treatment(28).After 5 mL of the venous blood was collected in each of the patients to detect the expression of MDR1,36 cases received flunarizine 5 mg, po,qn,for 7-8 wk,as an add-on antiepileptic drug.Other 28 cases was given placebo (vitamin B6)10mg,po,qⁿ,for 7-8 wk.All patients were to re-examine the MDR1 mRNA with the same method.Results All rats came to epileptic seizure about 2-10minutes after intraperitoneal injection of KA.At last,the dead number was 8 and there were 2 rats failing.Expression of mdr1a and mdr1b mRNA in the hippocampus were increased significantly in the EP+LEV group and EP group compared with control group (P<0.001).The EP group was increased compared with EP+LEV group(P<0.05). control+LEV group have little affect on the expression of mdr1a and mdr1b mRNA in the hippocampus than control group(P >0.05).Moreover,recurrent seizures causes significant reduction in brain weight:the weight of hippocampus was decreased in mean brain weight of 15.3%(0.137±0.018 vs 0.158±0.015,P<0.01).LEV led to a increase in weight of brain of 8.1%(0.149±0.013 vs 0.137±0.018)in EP group,but it also resulted in a slight decrease in weight of brain of 3.5%(0.153±0.017 vs 0.158±0.015,P>0.05)in control+LEV group.The expression level of MDR1 mRNA was elevated in the intractable epilepsy, compares with control group(P <0.01).After treatment with flunarizine about 7-8 wk,20 of 36(55.56%)patients were clinically effective in flunarizine group.At the same time,there was only 2 patient in placebo group(7.14%)effectively.The expression of MDR1 mRNA was decreased in the re-examined 36 cases in flunarizine group,and increased in placebo group,compared with control group.There were 2 cases showing somnolence and 1 case feeling dizziness,the incidence of adverse effect is 8.33%.Conclusion Frequent seizures result in overexpression of mdr1a and mdr1b mRNA in the hippocampus.The expression of mdr1a and mdr1b mRNA in the hippocampus descreased after treatment with levetiractam,so levetiractam could probably lower the level of mdr mRNA.It can promote the development of hippocampus in epileptic rats,but slightly reduces the weight of hippocampus in normal rats.The expression of MDR1 mRNA in peripheral blood is parallel to that in brain,so it can be regarded as an index to evaluate the expression of MDR1 mRNA.Flunarizine is effective,as an add-on therapy in intractable epilepsy with MDR1.It's mechanism to treat intractable epilepsy may involve in reversing the expression of MDR1 mRNA. At the same time,we find the side effects of flunarizine in low dose are very small,and it can be used as add-on therapy in children intractable epilepsy.