Title:Increased Cyclic Adenosine Monophosphate Responsive Element is Closely
Associated with the Pathogenesis of Drug-resistant Epilepsy
Volume: 21
Issue: 1
Author(s): Jing-Xuan Li, Dai Shi, Si-Ying Ren and Guo-Feng Wu*
Affiliation:
- Clinical College of Guizhou, Medical University, Guiyang, Guizhou, 561113, China
- Department of Emergency, Affiliated Hospital/
Clinical College of Guizhou Medical University, Guiyang, Guizhou, 561113, China
Keywords:
Epilepsy, drug-resistant epilepsy, CREB, GABAA receptor, γ-aminobutyric, status epilepticus.
Abstract:
Background: Drug-resistant epilepsy (DRE) is a refractory neurological disorder.
There is ample evidence that suggest that γ-aminobutyric acid-a (GABAA) receptors could be
one of the mechanisms responsible for the development of drug resistance in epilepsy. It is also
known that the cAMP response element binding protein (CREB) plays a possible key role in the
transcriptional regulation of GABAA.
Objective: This study explores the role of CREB in the development of DRE and the effect of
CREB on GABA-related receptors in DRE.
Methods: The CREB expression was increased or decreased in the hippocampus of normal rats
by lentiviral transfection, who then underwent the lithium-pilocarpine-induced epilepsy model.
Phenobarbital (PB) sodium and carbamazepine (CBZ) were used to select a drug-resistant epileptic
model. The expression levels of GABAA receptor α1, β2, and γ2 subunits and CREB protein
were measured in the rat hippocampus by western blot and fluorescent quantitative PCR.
Results: The frequency and duration of seizures increased in the overexpression group compared
to that in the control group. In addition, the severity, frequency, and duration of seizures decreased
in the group with decreased expression. The hippocampus analysis of the expression
levels of the CREB protein and CREB mRNA yielded similar findings. Altering the CREB protein
expression in the rat hippocampus could negatively regulate the expression and transcript
levels of GABAA receptors α1, β2, and γ2, suggesting that CREB may serve as a potential target
for the development of treatment protocols and drugs for epilepsy.
Conclusion: Our study shows that enhanced CREB expression promotes the development of
DRE and negatively regulates GABAA receptor levels and that the inhibition of CREB expression
may reduce the incidence of DRE.
