Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin
Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin
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DOI：
10.1111/epi.16434
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发表时间：
2020-02-06
期刊：
影响因子：
5.6
通讯作者：
Simeone, Kristina A.
中科院分区：
文献类型：
--
作者：
Iyer, Shruthi H.;Aggarwal, Ankita;Simeone, Kristina A.
目的癫痫猝死（sudden unexpected death in epilepsy，SUDEP）患者在发生猝死前，会出现最终全身强直阵挛发作（generalized tonic-clonic seizure，GTCS）、快速通气、呼吸暂停、心动过缓、终末呼吸暂停和心搏停止。进行性病理生理学是否发展并增加SUDEP的风险仍不清楚。在这里，我们确定了（a）低风险和高风险基因敲除（KO）小鼠的心率，呼吸频率和血氧饱和度（SaO（2））;和（B）阻断食欲素受体，一种心肺神经调节剂，是否影响心肺功能小鼠或高风险KO小鼠的寿命。采用无创气道力学技术测定呼吸功能。在用双重食欲素受体拮抗剂（DORA，100 mg/kg）急性治疗后，在受试者中确定食欲素的作用。食欲素神经元在外侧下丘脑的数量进行了测定与免疫组化。结果间歇性心动过缓是更普遍的高风险KO小鼠，效果，这可能是由于增加副交感神经驱动。高风险KO小鼠在外侧下丘脑中有更多的食欲素神经元。阻断食欲素受体对KO小鼠的心率有不同的影响，但对野生型（WT）小鼠没有影响。当DORA给药增加心率时，它还降低心率变异性、呼吸频率和/或呼吸不足-呼吸暂停。阻断食欲素受体可通过直接或间接机制阻止乙酰甲胆碱（MCh）诱导的KO小鼠呼吸频率增加，并减少MCh诱导的癫痫发作。DORA改善了间歇性缺氧KO小鼠的氧饱和度。高风险KO小鼠具有独特的心肺表型，其特征在于五个相互依赖的终点的进行性变化。阻断食欲素受体可以减弱这些终点中的一些并延长寿命，支持在这种临床前SUDEP模型中存在干预机会窗口的观点。
Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic-clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO(2)) in low-risk and high-risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high-risk KO mice.Methods Heart rate and SaO(2) were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry.Results Intermittent bradycardia was more prevalent in high-risk KO mice, an effect that may be the result of increased parasympathetic drive. High-risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild-type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea-apnea. Blocking orexin receptors prevented the methacholine (MCh)-induced increase in breathing frequency in KO mice and reduced MCh-induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high-risk KO mice increased longevity.Significance High-risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.