Prevention of seizure-induced sudden death by periaqueductal gray stimulation

项目摘要 癫痫是一种常见而严重的大脑疾病，可能是致命的。猝死的风险是24 癫痫患者比普通人群更大的倍数，原因不明的猝死 在潜在寿命损失年数中，癫痫(SUDEP)在神经系统疾病中排名第二。那里 目前还没有针对这种毁灭性的癫痫后遗症的预防性治疗。因此，研究 研究预防SUDEP的机制至关重要，正如NINDS所指出的那样 基准。大多数亲眼目睹的SUDEP病例死亡是由全身性强直-阵挛发作引起的 (GTCS)导致终末性呼吸暂停。我们建立了SUDEP的DBA/1小鼠模型。 模拟人类SUDEP，因为它表现出GTCS和癫痫诱导的呼吸骤停(S-IRA)， 直接导致死亡。其他几个实验室最近也使用了这种模型。DBA/1小鼠的实验研究 导致了SUDEP的5-羟色胺理论的发展，并在#年得到了积极的支持 最近对癫痫患者的研究。这个由我们实验室首先提出的假说，部分是基于 研究发现，加强5-羟色胺作用的治疗可以阻断癫痫导致的死亡。这个 检验这一假说的SUDEP模型包括Dravet小鼠，该模型 德拉韦综合征，人类癫痫的一种难治性形式，有很高的SUDEP风险。杜威小鼠 经过基因改造以模仿人类的德拉维氏综合症，也显示了S的猝死- 爱尔兰共和军。DRAVET小鼠表现出热诱导癫痫发作，通过及时复苏可以防止死亡 与DBA/1小鼠相似。重要的是，在癫痫患者中，非致命性但显著的呼吸缺陷 常发生在GTCS之后，而后呼吸暂停是人类SUDEP最常见的原因。这 提案将利用DBA/1和Dravet小鼠测试SUDEP的预防措施。我们最近 DBA/1小鼠的神经成像研究提供了提示证据表明，特定的脑干 中脑导水管周围灰质(PAG)可能是预防癫痫致死的关键部位。PAG是 已知在弥补许多类型的非癫痫相关的呼吸缺陷方面起着关键作用。 PAG刺激目前用于治疗慢性疼痛，并将增强呼吸。我们 已经初步评估了刺激PAG的效果，并发现它可以增强老年人的呼吸 麻醉DBA/1小鼠。因此，我们将探索PAG电刺激是否会增强 Dba/1和Dravet小鼠致痫后的呼吸及逆转S-IRA。 目的1：探讨适时电刺激PAG能否预防听源性癫痫发作 呼吸骤停(S-IRA)对SUDEP DBA/1小鼠模型的影响 目的2：观察适时PAG电刺激能否预防癫痫大鼠癫痫猝死 高温诱发小鼠SUDEP模型的建立。

PROJECT ABSTRACT Epilepsy is a common and serious brain disorder that can be fatal. The risk of sudden death is 24 times greater in epilepsy patients than the general population, and sudden unexplained death in epilepsy (SUDEP) ranks 2nd highest among neurologic diseases in potential years of life lost. There are currently no preventative treatments for this devastating epilepsy sequelae. Therefore, research into mechanisms for prevention of SUDEP is critically important, as indicated in the NINDS benchmarks. Death in most witnessed SUDEP cases results from generalized tonic-clonic seizures (GTCS) leading to terminal apnea. We have developed the DBA/1 mouse model of SUDEP, which mimics human SUDEP in that it exhibits GTCS and seizure-induced respiratory arrest (S-IRA) that leads directly to death. Several other labs have recently utilized this model. Research in DBA/1 mice led to the development of the serotonin theory of SUDEP, which has received positive support in recent studies in epilepsy patients. This hypothesis, first proposed by our lab is based, in part, on the findings that treatments which enhance the action of serotonin block seizure-induced death. The SUDEP models in which the hypothesis has been tested include the Dravet mice, which model Dravet syndrome, an intractable form of human epilepsy that has a high risk for SUDEP. Dravet mice are genetically modified to mimic human Dravet syndrome and also show sudden death due to S- IRA. Dravet mice exhibit heat-induced seizures, and death can be prevented by timely resuscitation similar to DBA/1 mice. Importantly, in epilepsy patients non-fatal but significant respiratory deficits frequently occur after GTCS, and postictal apnea is the most common cause of human SUDEP. This proposal will utilize DBA/1 and Dravet mice to test preventative measures for SUDEP. Our recent neuroimaging studies in DBA/1 mice have provided suggestive evidence that a specific brainstem site- the periaqueductal gray (PAG)-may be critical in preventing seizure-induced death. The PAG is known to play a critical role to compensate for many types of non-epilepsy-related respiratory deficits. PAG stimulation is currently used in patients to treat chronic pain and will enhance respiration. We have preliminarily evaluated the effects of PAG stimulation and found that it enhances respiration in anesthetized DBA/1 mice. Therefore, we will explore if PAG electrical stimulation will enhance respiration and reverse S-IRA following seizures induced in behaving DBA/1 and Dravet mice. Aim 1: To explore if timely electrical stimulation of the PAG can prevent audiogenic seizure-induced respiratory arrest (S-IRA) and death in the DBA/1 mouse model of SUDEP. Aim 2: To examine if timely PAG electrical stimulation can prevent seizure-induced sudden death in the Dravet mouse model of SUDEP induced by elevated temperature.