Insulin/IGF-1信号调控能量代谢和脑电活动在抗癫痫发作与形成中的作用及机制

Epileptic seizure is a process that includes the aggregation, eruption and depletion of energy. To interfere or block timely the energy for epileptic seizure, it may be the key factor by that stops the epileptiform discharge generation, transmission and termination. It is unclear that was an effective therapeutic strategy for energy metabolism of neuron which interferes with the process of development of epileptic seizure. The previous research of applicant has found that IGF-1 receptor inhibitor suppress seizure activities by inhibiting the downstream ERK1/2 and AKT signal. Moreover, the effect is more significant that Insulin/IGF-1 receptor inhibitors OSI-906 inhibiting the seizure behavior and epileptiform discharge, and similar to diazepam terminates the epileptic attack. To explore the OSI- 906, microRNA-9 agomir and antagomir intervention Insulin/IGF 1 receptor signal on the acute chronic epileptic seizures and the chronic epileptogenesis, this project intends to adopt 18 FDG PET-CT, the multichannel recording technique in vivo, molecular biology, pathology morphology and behavioristics for observing the brain electrical activity, energy metabolism, mitochondrial damage, neuron degeneration and necrosis. Future work, we measures ERK1/2 and AKT which is Insulin/IGF-1 receptor downstream signal. We will reveal the changes of energy metabolism and electrical activities in the seizure and progress from the level of molecules and electrical physiology. This study is expected to find the new drug targets and treatment plan for anti-epileptic seizures and anti-epileptogenesis.

癫痫发作是一次能量聚集、爆发和耗竭过程，及时干扰或阻断痫性发作所需能量，可能是阻止痫性活动产生、传播和终止的关键，但目前癫痫发作与形成过程神经元能量代谢的调控靶点和机制尚不清楚。申请人前期研究发现IGF-1R抑制剂通过下游ERK1/2及AKT信号抑制痫性发作，而Insulin/IGF-1受体抑制剂 OSI-906抑制发作行为和痫性放电效果更显著。本项目拟采用18FDG-PET、在体多通道记录技术、分子生物学、病理形态学和行为学观察，探讨OSI-906、miRNA-9 agomir和antagomir干预对急性癫痫发作和慢性癫痫形成过程行为学、脑电活动、能量代谢、线粒体损失、神经元变性坏死和ERK1/2及AKT信号的影响；以明确Insulin/IGF-1受体信号在癫痫发作与形成过程中的作用及其机制。本研究成果有望为抗癫痫发作与抗癫痫形成的临床治疗提供新的药物作用靶点和治疗方案。

鼻内胰岛素对多种神经系统疾病具有神经保护作用。但鼻内胰岛素是否影响癫痫的活动以及它是否对癫痫性疾病有神经保护作用仍是未知的。在这里，我们证明了低剂量鼻内给药可以抑制kainic acid (KA)或pentylenetetrazole (PTZ)诱导的小鼠急性癫痫发作和减少癫痫放电活动，可能是通过减轻癫痫诱发的海马区谷氨酸的增加来实现的。同时，鼻内胰岛素增加了GABA水平和海马神经元电活动，可能影响海马的兴奋性。在慢性KA诱发的癫痫中，低剂量的鼻内胰岛素降低了自发性发作和癫痫放电的频率，同时增加了theta能量，从而改善了空间记忆。大剂量的鼻内胰岛素增加了癫痫发作的频率，但并没有加重认知障碍，这表明癫痫发作的频率可能与认知功能受损无关。总之，我们的研究结果表明，低剂量的鼻内胰岛素可以抑制癫痫发作，改善癫痫小鼠的认知障碍，提示鼻内胰岛素可以改善癫痫动物的学习和记忆功能；但大剂量可能会增加癫痫发作的风险。

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