Increased Cyclic Adenosine Monophosphate Responsive Element is Closely Associated with the Pathogenesis of
Jing-Xuan Li1, Dai Shi2, Si-Ying Ren1,3
1Clinical College of Guizhou, Medical University, Guiyang, Guizhou, 561113, China.
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.
Insights
Enhanced cAMP response element binding protein (CREB) expression promotes drug-resistant epilepsy (DRE) by negatively regulating GABA-A receptors. Inhibiting CREB may reduce DRE incidence, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
Background:
- Drug-resistant epilepsy (DRE) is a challenging neurological condition.
- γ-aminobutyric acid-a (GABAA) receptors are implicated in epilepsy drug resistance.
- cAMP response element binding protein (CREB) is a key regulator of GABAA transcription.
Purpose of the Study:
- To investigate the role of CREB in DRE development.
- To examine CREB's effect on GABA-related receptors in DRE.
Main Methods:
- CREB expression was manipulated in rat hippocampus via lentiviral transfection.
- A lithium-pilocarpine-induced epilepsy model was established.
- GABAA receptor subunit expression (α1, β2, γ2) and CREB levels were quantified using western blot and qPCR.
Main Results:
- Increased CREB expression exacerbated seizure frequency and duration.
- Decreased CREB expression reduced seizure severity, frequency, and duration.
- CREB levels were found to negatively regulate GABAA receptor expression and transcript levels.
Conclusions:
- Enhanced CREB expression promotes DRE.
- CREB negatively regulates GABAA receptor expression.
- Inhibiting CREB may offer a therapeutic strategy for DRE.
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