Effect Of Berberine On The Expression Of P-glycoprotein In The Epileptic Rats’ Brain And Its Mechanism

Background: P-glycoprotein (P-gp) is one of the blood–brain barrier effluxtransporters that limit anti-epileptic drugs into the brain in drug resistant epilepsy(DRE) patients. Inhibition P-glycoprotein expression may become the new way totreat DRE. There was recent evidence that the brain inflammatory response maycontribute to the development of DRE. Our previous study showed that NF-κB playedan important role in the expression in epileptogenic rat brain. Inhibition the activity ofNF-κB could significantly reduce the expression of P-gp. Berberine (BBR) is acommon drug to treat inflammation. BBR could inhibit the activity of NF-κB andtreat infection、tumor and stroke. However, whether BBR can treat DRE by inhibitionthe inflammation and reduce the expression of P-gp via NF-κB signal pathway hasnot been fully elucidated.Objective: This study was aimed to investigate whether BBR can inbibit NF-κBactivity and reduce P-gp expression in the brain of epileptic rats, Meanwhile, theeffect of BBR on the seizure severity、brain damage and the activation of microglia ofepileptic rats was also focused on.Methods Male SD rats were randomly divided into sham operation group (Shamgroup, n=8), epilepsy rats group (EP group, n=9), epilepsy rats intervened with10mg/kg BBR group (BBR10group, n=9)、20mg/kg BBR group (BBR20group, n=9)and40mg/kg BBR group (BBR40group, n=9). The epilepsy rats were established byinjecting Kainic acid (KA) into the rat hippocampus and the rats of BBR groups weregiven BBR by intraperitoneal injection48h、24h prior to KA and6h after KA. Thelatency period of epileptic seizure(the time from KA injection to1thⅣgrade seizure) and the seizure severity (the time from the first to6th≥Ⅳgrade seizure) wereobserved in each group. After24h of the operation, they were sacrificed.Immuno-histochemical method was used to detect and compare P-gp、p65(onerepresentative subunit of NF-κB)、 CD11b expression and brain damage inhippocampus CA3area of each rat.Results(1)The epileptic seizure latency and the seizure severity of BBR10group were longerthan that of EP group, but there were no significant differences. The epileptic seizurelatency of BBR20and BBR40group [(66.11±5.90)min、(76.33±9.11)min] werelonger than EP group [(41.78±10.45)min](P<0.05). The time from the first to6th≥Ⅳgrade seizure of BBR20and BBR40group [(26.67±6.67)min、(42.00±7.73)min] were prolonged than that of EP group [(9.44±4.25)min](P<0.05).(2)Compared with the sham group, the expression of NF-κBp65and P-gp wassignificantly up-regulated in hippocampus CA3area of EP group. By contrast, theexpression of P-gp and NF-κBp65was lowered in BBR20group and BBR40groupthan that in EP group, and there were statistically significant differences (P<0.05).But there were no statistically significant differences between BBR10group and EPgroup.(3)Compared with the EP group, the number of the survival neurons significantlyincreased in BBR10、BBR20and BBR40group (P<0.05)(4)Compared with the sham group, the expression of CD11b in EP group significantlyincreased. Compared with the EP group, the expression of CD11b in BBR40groupsignificantly reduced.Conclusions:(1)BBR reduced the seizure susceptibility and severity、brain damage and theactivation of microglia of KA induced epileptic rats during the24h observation period.(2)BBR can treat epilepsy by inhibition the inflammation and reduce the expressionof P-gp via NF-κB signal pathway.