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
CNS & Neurological Disorders - Drug Targets,
Nian Yu, Hao Liu, Yan-Fang Zhang, Ling-Ying Su, Xin-Hong Liu, Le-Chao Li, Jin-Bo Hao, Xian-Jing Huang and Qing DiAffiliation:
Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, 264 Guangzhou Road, Nanjing, Jiangsu, 210009, China.
AbstractMultidrug 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 pathway.
Epilepsy, P-glycoprotein, nuclear factor-kappa B, inhibitory κB kinase subunit β, multidrug resistance.
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