Effects of Brain IKKβ Gene Silencing by Small Interfering RNA on P-Glycoprotein Expression and Brain Damage in the Rat Kainic Acid-Induced Seizure Model
Multidrug resistance mediated by over-expression of P-glycoprotein (P-gp) in brain is an important mechanism
accounting for the drug-therapy failure in epilepsy. Over-expression of P-gp in epilepsy rat brain may be regulated by
inflammation and nuclear factor-kappa B (NF-κB) activation. Inhibitory κ B kinase subunit β (IKKβ) is an up-stream
molecular controlling NF-κB activation. With the small interfering RNA (siRNA) technique and kainic acid (KA)-induced
rat epileptic seizure model, the present study was aimed to further evaluate the role of NF-κB inhibition, via blocking
IKKβ gene transcription, in the epileptic brain P-gp over-expression, seizure susceptibility, and post-seizure brain
damage. siRNA targeting IKKβ was administered to rats via intracerebroventricular injection before seizure induction by
KA microinjection; scrambled siRNA was used as control. Brain mRNA and protein levels of IKKβ and P-gp were
detected by RT-PCR and immunohistochemistry. NF-κB activity was measured by electrophoretic mobility shift assay.
Latency to grade III or V seizure onset was recorded, brain damage was evaluated by neuronal cell counting and
epileptiform activity was monitored by electroencephalography. IKKβ siRNA pre-treatment inhibited NF-κB activation
and abolished P-gp over-expression in KA-induced epileptic rat brain, accompanied by decreased seizure susceptibility.
These findings suggested that epileptogenic-induced P-gp over-expression could be regulated by IKKβ through the NF-κB
Keywords: Epilepsy, P-glycoprotein, nuclear factor-kappa B, inhibitory κB kinase subunit β, multidrug resistance.
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