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HDAC4 gene silencing alleviates epilepsy by inhibition of GABA in a rat model

Authors Zhang YN, Dong HT, Duan L, Niu L, Yuan GQ, Dai JQ, Hou BR, Pan YW

Received 27 July 2018

Accepted for publication 4 November 2018

Published 4 February 2019 Volume 2019:15 Pages 405—416

DOI https://doi.org/10.2147/NDT.S181669

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Yu-Ping Ning


Yinian Zhang,1,2,* Hua-Teng Dong,3,* Lei Duan,1,2 Liang Niu,1,2 Guo-Qiang Yuan,1,2 Jun-Qiang Dai,1,2 Bo-Ru Hou,1,2 Ya-Wen Pan1,2

1Department of Neurosurgery and Laboratory of Neurosurgery, Lanzhou University Second Hospital, Lanzhou 730030, People’s Republic of China; 2Institute of Neurology, Lanzhou University, Lanzhou 730030, People’s Republic of China; 3Department of Pediatric Neurology, Gansu Provincial Maternity and Child-Care Hospital, Lanzhou 730050, People’s Republic of China

*These authors contributed equally to this work

Objectives: Despite the availability of effective antiepileptic drugs, epileptic patients still suffer from intractable seizures and adverse events. Better control of both seizures and fewer side effects is needed in order to enhance the patient’s quality of life. We performed the present study with an attempt to explore the effect that HDAC4 gene silencing would have on epilepsy simulated by model rats. Furthermore, the study made additional analysis on the relativity of the HDAC4 gene in regard to its relationship with the gamma-aminobutyric acid (GABA) signaling pathway.
Materials and methods: Tremor rats were prepared in order to establish the epilepsy model. The rats would go on to be treated with si-HDAC4 in order to identify roles of the HDAC4 in levels of GABAARα1, GABAARα4, GAD65, GAT-1, and GAT-3. Finally, both electroencephalogram behavior and cognitive function of the rats following the treatment of si-HDAC4 were observed.
Results: Levels of the GABAARα1 and GABAARα4 showed an evident increase, while GAD65, GAT-1, and GAT-3 displayed a decline in the epilepsy rats treated with the aforementioned si-HDAC4 when compared with the epilepsy rats. After injection of si-HDAC4, the epilepsy rats presented with a reduction in seizure degree, latency and duration of seizure, amount of scattered epileptic waves, and occurrence of epilepsy, with an improvement in their cognitive function.
Conclusion: The study highlighted the role that HDAC4 gene silencing played in easing the cases of epilepsy found in the model rats. This was shown to have occurred through the upregulation of both GABAARα1 and GABAARα4 levels, as well as in the downregulation of GAD65, GAT-1, and GAT-3 levels. The evidence provided shows that the HDAC4 gene is likely to present as a new objective in further experimentation in the treatment of epilepsy.

Keywords: epilepsy, HDAC4, gene silencing, GABA receptor, GABA transporter, seizures


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