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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.
- Source :
-
CNS & neurological disorders drug targets [CNS Neurol Disord Drug Targets] 2014; Vol. 13 (4), pp. 661-72. - Publication Year :
- 2014
-
Abstract
- 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 pathway.
- Subjects :
- Animals
Brain pathology
Disease Models, Animal
Gene Expression
Kainic Acid
Male
NF-kappa B metabolism
Neurons pathology
Neurons physiology
Rats, Sprague-Dawley
Seizures pathology
Transcription, Genetic
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Brain metabolism
I-kappa B Kinase genetics
I-kappa B Kinase metabolism
RNA Interference
RNA, Small Interfering metabolism
Seizures metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1996-3181
- Volume :
- 13
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- CNS & neurological disorders drug targets
- Publication Type :
- Academic Journal
- Accession number :
- 24040792
- Full Text :
- https://doi.org/10.2174/18715273113129990106