Neuron-restrictive silencer factor is not required for the antiepileptic effect of the ketogenic diet

Authors

  • Xiao-Ling Hu,

    1. Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Search for more papers by this author
  • Xuewen Cheng,

    1. Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Search for more papers by this author
  • Jian Fei,

    1. School of Life Sciences and Technology, Tongji University, Shanghai, China
    2. Shanghai Research Center for Model Organisms, Shanghai, China
    Search for more papers by this author
  • Zhi-Qi Xiong

    1. Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Search for more papers by this author

Address correspondence to Jian Fei, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China. E-mail: Jfei@mail.tongji.edu.cn
and
Zhi-Qi Xiong, Institute of Neuroscience, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. E-mail: xiongzhiqi@ion.ac.cn

Summary

Purpose:  The ketogenic diet (KD) has been used as an effective antiepileptic treatment for nearly a century. Inhibition of glycolysis and increased levels of ketone bodies are both known to contribute to the antiepileptic effects of the KD. Neuron-restrictive silencer factor (NRSF), also known as RE-1 silencing transcription factor (REST), is implicated in the antiepileptic effects of the glycolytic inhibitor 2-deoxy-d-glucose (2DG). Glycolytic inhibition is a common feature of the KD and 2DG treatment, leading to the hypothesis that NRSF might also be involved in the antiepileptic effect of the KD. To test this hypothesis, the present study was designed to investigate the role of NRSF in the antiepileptic effect of 2DG, the KD, and acetone in vivo.

Methods:  Kindling was used as a model to test the antiepileptic effects of 2DG, the KD, and acetone on control and NRSF conditional knockout mice (NRSF-cKO; from the intercross of CamKIIα-iCre and NRSF exon 2 floxed mice). After recovery from electrode implantation, adult mice were stimulated twice a day at afterdischarge threshold (ADT) current intensity. In the 2DG- (500 mg/kg) and acetone- (10 mmol/kg) treated groups, drugs were injected intraperitoneally 20 min before each stimulus. In the 2DG group, mice were pretreated with intraperitoneal injections for 3 days in addition to the injections administered before the regular kindling stimulation. In the KD group, mice were fed the KD instead of a control diet until the end of stimulations.

Key Findings:  Compared with control mice, the antiepileptic effect of 2DG was abolished in NRSF-cKO mice, indicating that NRSF is required for the antiepileptic effect of 2DG. In the KD-fed group, kindling development was retarded in both control and NRSF-cKO mice. In the acetone-treated group, inhibition of kindling-induced epileptogenesis was observed in both control and NRSF-cKO mice, similar to the action of the KD.

Significance:  These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet.

Ancillary