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 癫痫新出现的数据表明，很大一部分SUDEP是由于呼吸道感染引起的呼吸道疾病。 逮捕了关于癫痫发作如何导致呼吸暂停，谁处于最高风险以及什么可能导致呼吸暂停， 我们已经发现，在两个遗传小鼠中， 人SUDEP模型（Scn 1aR 1407 X和Scn 8aN 1768 D小鼠）。我们的数据显示癫痫发作 从杏仁核到脑干的投射导致中枢性呼吸暂停和CO2的短暂缺陷 稳态和5-HT神经元功能。这得到了数据的支持，数据显示5-HT神经元， 其是刺激呼吸的中枢CO2/pH化学感受器，在癫痫发作期间被抑制。中央 目前的假设是癫痫发作损害CO2化学感受，部分是通过抑制5-HT 神经元，这增加了癫痫发作成为致命的风险。我们还发现， 与牛奶乳清一起使用会大大降低SUDEP的风险，这可能是由于5-HT的增加。 本提案将使用Scn 1aR 1407 X和Scn 8aN 1768 D小鼠来实现以下具体目标。1)确定 CO2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CO2 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， 癫痫发作导致发作后通气量大幅下降， （HCVR），以及体温的短暂下降。所有这三种自我平衡的脑干功能 由血清素神经元控制我们将使用24小时监测脑电图，肌电图，心电图，体积描记法，身体 温度和视频在小鼠癫痫监测单元（EMU），以研究由于自发性 癫痫发作2)我们将明确5-HT系统功能障碍对发作后通气不足和呼吸暂停的作用。 工作假设：5-羟色胺系统受损导致发作和发作后通气不足。减少 脑5-HT已显示降低HCVR。我们将增加或减少小鼠脑5-HT， 测量自发性猝死的频率和HCVR的发作后变化。3)定义 乳清预防SUDEP的机制。工作假设：SUDEP风险通过乳清降低， 脑5-HT和/或CO2化学感受性增加。我们建议研究乳清是否有效， 预防Scn 8aN 1768 D、Kcna 1-null和DBA/1小鼠中的尿素诱导的死亡。我们将研究乳清是否 防止抑制HCVR与癫痫发作。我们将研究哪些成分对 存活，以及它们是否通过5-HT的变化起作用。预期的结果是二氧化碳化学感受 将被确立为SUDEP机制的核心，以及乳清如何保护它。 影响是乳清可能是一种新的和安全的方法，以防止SUDEP的目标机制， 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.