Prevention of SUDEP by milk whey: Role of CO2 chemoreception and serotonin

摘要 癫痫猝死（SUDEP）是难治性癫痫患者最常见的死亡原因 癫痫。新数据表明，很大一部分 SUDEP 是由癫痫发作引起的呼吸系统疾病引起的。 逮捕。关于癫痫发作如何导致呼吸暂停、谁的风险最高以及可能发生什么，人们的知识还存在差距。 为防止它而采取的措施。我们发现两只基因小鼠的癫痫发作后死亡是由于癫痫发作引起的呼吸暂停 人类 SUDEP 模型（Scn1aR1407X 和 Scn8aN1768D 小鼠）。我们的数据表明癫痫发作会激活 从杏仁核到脑干的投射导致中枢性呼吸暂停和二氧化碳的短暂缺陷 体内平衡和血清素 (5-HT) 神经元功能。数据支持这一点，显示 5-HT 神经元， 它们是刺激呼吸的中枢 CO2/pH 化学感受器，在癫痫发作期间受到抑制。中央 目前提议的假设是癫痫发作会损害 CO2 化学感受，部分是通过抑制 5-HT 神经元，这增加了癫痫发作致命的风险。我们还发现，饮食补充 与牛奶乳清一起食用可大大降低 SUDEP 的风险，这可能是由于 5-HT 的增加所致。 该提案将使用 Scn1aR1407X 和 Scn8aN1768D 小鼠来实现以下具体目标。 1）确定 二氧化碳化学感受受损在致命性发作后呼吸暂停中的作用。工作假设：癫痫发作抑制二氧化碳 化学感受，这会增加致命性呼吸暂停的风险。我们的初步数据表明，广义 癫痫发作导致发作后通气量大幅减少，高碳酸血症通气反应降低 （HCVR），以及体温短暂下降。所有这三种稳态脑干功能都是 由血清素神经元控制。我们会24小时监测脑电图、肌电图、心电图、体积描记法、身体 小鼠癫痫监测装置 (EMU) 中的温度和视频，用于研究自发性癫痫引起的变化 癫痫发作。 2) 我们将定义 5-HT 系统功能障碍对发作后通气不足和呼吸暂停的影响。 工作假设：5-HT 系统受损会加剧发作期和发作后通气不足。减少 大脑 5-HT 已被证明可以降低 HCVR。我们将增加或减少小鼠大脑中的 5-HT 测量自发性猝死的频率以及 HCVR 的发作后变化。 3) 定义 乳清预防 SUDEP 的机制。工作假设：乳清通过以下途径降低 SUDEP 风险： 大脑 5-HT 和/或 CO2 化学感受增加。我们建议检查乳清是否有效 预防 Scn8aN1768D、Kcna1-null 和 DBA/1 小鼠癫痫发作引起的死亡。我们将检查乳清是否 防止 HCVR 抑制引起癫痫发作。我们将检查哪些成分具有保护作用 生存，以及它们是否通过 5-HT 的变化发挥作用。预期结果是 CO2 化学感受 将被确立为 SUDEP 机制以及乳清如何预防 SUDEP 的核心。更广泛的 影响是乳清可能是一种新的、安全的方法来预防针对潜在机制的 SUDEP 发作后呼吸停止。

Abstract Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Emerging data indicate that a substantial percentage of SUDEP is due to seizure-induced respiratory arrest. There is a gap in knowledge about how seizures cause apnea, who is at highest risk and what can be done to prevent it. We have found that postictal death is due to seizure-induced apnea in two genetic mouse models of human SUDEP (Scn1aR1407X and Scn8aN1768D mice). Our data indicate that seizures activate projections from the amygdala to the brainstem causing central apnea, and transient defects in CO2 homeostasis and serotonin (5-HT) neuron function. This is supported by data showing that 5-HT neurons, which are central CO2/pH chemoreceptors that stimulate breathing, are inhibited during seizures. The central hypothesis of the current proposal is that seizures impair CO2 chemoreception, in part by inhibiting 5-HT neurons, which increases the risk of a seizure becoming fatal. We have also found that a diet supplemented with milk whey causes a large reduction in the risk of SUDEP, and this may be due to an increase in 5-HT. This proposal will use Scn1aR1407X and Scn8aN1768D mice to carry out the following specific aims. 1) Determine the role of impaired CO2 chemoreception in fatal post-ictal apnea. Working hypothesis: Seizures inhibit CO2 chemoreception, which increases the risk of fatal apnea. Our preliminary data indicate that generalized seizures cause a large post-ictal decrease in ventilation, a decrease in the hypercapnic ventilatory response (HCVR), and a transient drop in body temperature. All three of these homeostatic brainstem functions are controlled by serotonin neurons. We will use 24-hour monitoring of EEG, EMG, EKG, plethysmography, body temperature and video in a mouse epilepsy monitoring unit (EMU) to study changes due to spontaneous seizures. 2) We will define the contribution of 5-HT system dysfunction to postictal hypoventilation and apnea. Working hypothesis: Impairment of the 5-HT system worsens ictal and post-ictal hypoventilation. A decrease in brain 5-HT has been shown to decrease the HCVR. We will increase or decrease brain 5-HT in mice and measure the frequency of spontaneous sudden death, and postictal changes in the HCVR. 3) Define the mechanisms by which whey prevents SUDEP. Working hypothesis: SUDEP risk is reduced by whey via an increase in brain 5-HT and/or CO2 chemoreception. We propose to examine whether whey is effective in preventing seizure-induced death in Scn8aN1768D, Kcna1-null and DBA/1 mice. We will examine whether whey prevents inhibition of the HCVR with seizures. We will examine which components have a protective effect on survival, and whether they act through changes in 5-HT. The expected outcome is that CO2 chemoreception will be established as central to the mechanisms of SUDEP and to how whey protects against it. The broader impact is that whey may be a new and safe approach to prevent SUDEP that targets mechanisms underlying postictal respiratory arrest.