Zhu Xinjian, Dubey Deepti, Bermudez Camilo, Porter Brenda E
Department of Pediatrics and Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, U.S.A.
Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
Epilepsia. 2015 Dec;56(12):1870-8. doi: 10.1111/epi.13211. Epub 2015 Sep 30.
Current epilepsy therapies directed at altering the function of neurotransmitter receptors or ion channels, or release of synaptic vesicles fail to prevent seizures in approximately 30% of patients. A better understanding of the molecular mechanism underlying epilepsy is needed to provide new therapeutic targets. The activity of cyclic AMP (cAMP) response element-binding protein (CREB), a major transcription factor promoting CRE-mediated transcription, increases following a prolonged seizure called status epilepticus. It is also increased in the seizure focus of patients with medically intractable focal epilepsy. Herein we explored the effect of acute suppression of CREB activity on status epilepticus and spontaneous seizures in a chronic epilepsy model.
Pilocarpine chemoconvulsant was used to induce status epilepticus. To suppress CREB activity, a transgenic mouse line expressing an inducible dominant negative mutant of CREB (CREB(IR) ) with a serine to alanine 133 substitution was used. Status epilepticus and spontaneous seizures of transgenic and wild-type mice were analyzed using video-electroencephalography (EEG) to assess the effect of CREB suppression on seizures.
Our findings indicate that activation of CREB(IR) shortens the duration of status epilepticus. The frequency of spontaneous seizures decreased in mice with chronic epilepsy during CREB(IR) induction; however, the duration of the spontaneous seizures was unchanged. Of interest, we found significantly reduced levels of phospho-CREB Ser133 upon activation of CREB(IR) , supporting prior work suggesting that binding to the CRE site is important for CREB phosphorylation.
Our results suggest that CRE transcription supports seizure activity both during status epilepticus and in spontaneous seizures. Thus, blocking of CRE transcription is a novel target for the treatment of epilepsy.
目前针对改变神经递质受体功能、离子通道功能或突触小泡释放的癫痫治疗方法，在约30%的患者中无法预防癫痫发作。需要更好地了解癫痫的分子机制，以提供新的治疗靶点。环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）是促进CRE介导转录的主要转录因子，在称为癫痫持续状态的长时间癫痫发作后其活性增加。在药物难治性局灶性癫痫患者的癫痫病灶中其活性也会增加。在此，我们探讨了在慢性癫痫模型中急性抑制CREB活性对癫痫持续状态和自发性癫痫发作的影响。
使用毛果芸香碱化学惊厥剂诱导癫痫持续状态。为了抑制CREB活性，使用了一种转基因小鼠品系，该品系表达具有丝氨酸133替换为丙氨酸的诱导型显性负突变体CREB（CREB(IR)）。使用视频脑电图（EEG）分析转基因和野生型小鼠的癫痫持续状态和自发性癫痫发作，以评估CREB抑制对癫痫发作的影响。
我们的研究结果表明，激活CREB(IR)可缩短癫痫持续状态的持续时间。在诱导CREB(IR)期间，慢性癫痫小鼠的自发性癫痫发作频率降低；然而，自发性癫痫发作的持续时间没有变化。有趣的是，我们发现激活CREB(IR)后磷酸化CREB Ser133的水平显著降低，这支持了之前的研究工作，表明与CRE位点的结合对CREB磷酸化很重要。
我们的结果表明，CRE转录在癫痫持续状态和自发性癫痫发作期间均支持癫痫发作活动。因此，阻断CRE转录是治疗癫痫的一个新靶点。
