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，相当大比例的SUDEP是由癫痫引起的呼吸引起的 逮捕。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，人们的认识存在差距 这样做是为了防止它。我们在两个遗传性小鼠中发现癫痫诱发的呼吸暂停是致病后死亡的原因 人SUDEP模型(Scn1aR1407X和Scn8aN1768D小鼠)。我们的数据显示癫痫发作激活 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一过性缺陷 动态平衡与5-羟色胺(5-HT)神经元功能。数据显示，5-羟色胺神经元， 它们是刺激呼吸的中枢二氧化碳/pH化学感受器，在癫痫发作期间受到抑制。中环 目前提出的假设是，癫痫发作损害了二氧化碳的化学接收，部分是通过抑制5-羟色胺 神经元，这增加了癫痫发作变得致命的风险。我们还发现，在饮食中补充 添加牛奶乳清可以大大降低SUDEP的风险，这可能是由于5-羟色胺的增加所致。 这项提案将使用Scn1aR1407X和Scn8aN1768D小鼠来实现以下具体目标。1)确定 二氧化碳化学感受障碍在致死性发作后呼吸暂停中的作用。工作假说：癫痫发作抑制二氧化碳 化学接收，这增加了致命呼吸暂停的风险。我们的初步数据表明，广义的 癫痫发作导致发作后通气量的大幅下降，即高碳酸血症的呼吸系统反应的下降。 (HCVR)，以及体温的短暂下降。这三种动态平衡脑干功能都是 由5-羟色胺神经元控制。我们将使用24小时监测EEG，EMG，EKG，体积描记，身体 温度和视频在小鼠癫痫监测单元(EMU)中研究自发引起的变化 癫痫发作。2)明确5-羟色胺系统功能障碍对后遗症低通气量和呼吸暂停的影响。 工作假设：5-羟色胺系统受损会加重发作期和发作期后的低通气量。减少了…… 脑内5-羟色胺已被证明可以降低HCVR。我们将增加或减少小鼠脑内5-羟色胺和 测量自发性猝死的频率，以及死亡后HCVR的变化。3)定义 乳清阻止SUDEP的机制。工作假设：SUDEP风险由乳清通过 大脑5-羟色胺和/或二氧化碳化学接收增加。我们建议研究乳清是否对 预防Scn8aN1768D、KcNA1基因缺失和DBA/1小鼠癫痫致死。我们将检查乳清是否 防止出现癫痫发作时对HCVR的抑制。我们将研究哪些成分具有保护作用 存活，以及它们是否通过5-羟色胺的变化而起作用。预期的结果是二氧化碳的化学接收 将被确立为SUDEP机制的核心，以及乳清如何预防它。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 后遗症呼吸停止。

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.