Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Epilepsia. 2011 Sep;52(9):1609-16. doi: 10.1111/j.1528-1167.2011.03171.x. Epub 2011 Jul 18.
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.
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.
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.
These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet.
生酮饮食（KD）作为一种有效的抗癫痫治疗方法已有近一个世纪的历史。众所周知，抑制糖酵解和增加酮体水平都有助于 KD 的抗癫痫作用。神经元限制沉默因子（NRSF），也称为 RE-1 沉默转录因子（REST），与糖酵解抑制剂 2-脱氧-D-葡萄糖（2DG）的抗癫痫作用有关。糖酵解抑制是 KD 和 2DG 治疗的共同特征，这导致了这样一种假设，即 NRSF 也可能参与 KD 的抗癫痫作用。为了验证这一假设，本研究旨在研究 NRSF 在 2DG、KD 和丙酮体内抗癫痫作用中的作用。
点燃作为模型来测试 2DG、KD 和丙酮对对照和 NRSF 条件敲除小鼠（NRSF-cKO；从 CamKIIα-iCre 和 NRSF 外显子 2 floxed 小鼠的杂交中获得）的抗癫痫作用。在电极植入后恢复期间，成年小鼠在发作后放电阈值（ADT）电流强度下每天刺激两次。在 2DG-（500mg/kg）和丙酮-（10mmol/kg）处理组中，药物在每次刺激前 20 分钟腹膜内注射。在 2DG 组中，除了在常规点燃刺激前给予注射外，还对小鼠进行了为期 3 天的腹膜内注射预处理。在 KD 组中，小鼠喂食 KD 代替对照饮食，直到刺激结束。
与对照小鼠相比，2DG 的抗癫痫作用在 NRSF-cKO 小鼠中被消除，表明 NRSF 是 2DG 抗癫痫作用所必需的。在 KD 喂养组中，对照和 NRSF-cKO 小鼠的点燃发展都被延迟。在丙酮处理组中，观察到抑制点燃诱导的癫痫发生在对照和 NRSF-cKO 小鼠中，与 KD 的作用相似。
这些发现表明，NRSF 抑制复合物对于生酮饮食的抗癫痫作用不是必需的。
