Title:Low-frequency Electrical Stimulation of the Hippocampus Plays a Role in
the Treatment of Pharmacoresistant Epilepsy by Blocking the PKA-CREB
Pathway
Volume: 20
Issue: 2
Author(s): Yuanxin Huang, Dai Shi, Guofeng Wu*, Likun Wang*Siying Ren
Affiliation:
- Department of Emergency, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
- School of Basic Medicine, Guizhou
Medical University, Guiyang, 550025, China
- Department of Emergency, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
Keywords:
Pharmacoresistant epilepsy, low frequency electrical stimulation, protein kinases A, CAMP response elementbinding protein, Gamma-aminobutyric acid, hippocampal neurons.
Abstract:
Objective: The objective of this study is to study the mechanism of Low frequency electrical
stimulation (LFS) in the treatment of drug-resistant epilepsy by regulating the protein kinase
A (PKA)-cAMP response element-binding protein (CREB) signaling pathway upstream of gamma
aminobutyric acid A (GABAA) receptor.
Methods: Primary hippocampal neurons were extracted and cultured from fetal rat brains and
randomly divided into the normal control group, PKA-CREB agonist group, and PKA-CREB
inhibitor group. Drug-resistant epileptic rats were established and randomly divided into the
pharmacoresistant group, LFS group, PKA-CREB agonist combined with hippocampal LFS group,
and PKA-CREB inhibitor combined with hippocampal LFS group. The normal rats were in
the normal control group and drug-sensitive rats were in the pharmacosensitive group. The seizure
frequency of epileptic rats was determined using video surveillance. The expression of
PKA, CREB, p-CREB, and GABAA receptor subunits α1 and β2 of each group were detected
using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting
assays.
Results: The in vitro expression levels of PKA, CREB, and p-CREB in the agonist group were
significantly higher than those in the normal control group (NRC group), while the expression levels
of GABAA receptor subunits α1 and β2 were significantly lower than those in the NRC group.
The expression levels of PKA, CREB, and p-CREB in the inhibitor group were significantly lower,
while the expression levels of GABAA receptor subunits α1 and β2 were significantly higher than
those in the NRC group. The in vivo seizure frequency was significantly lower in the LFS group
than in the pharmacoresistant group (PRE group). Compared to the LFS group, the seizure frequency
and the expression levels of PKA, CREB, and p-CREB in the rat hippocampus were significantly
higher, and the expression levels of GABAA receptor subunits α1 and β2 were significantly
lower in the agonist group. The results in the inhibitor group were exactly the opposite of those in
the agonist group.
Conclusion: The PKA-CREB signaling pathway is involved in the regulation of GABAA receptor
subunits α1 and β2. In addition, LFS plays an important role in increasing GABAA receptor expression
by regulating the PKA-CREB signaling pathway.
