Development and characterization of an autoresuscitation test for preclinical SUDEP models.

IF 6.6 1区 医学 Q1 CLINICAL NEUROLOGY
Epilepsia Pub Date : 2025-09-09 DOI:10.1111/epi.18623
Shruthi H Iyer, Jillian E Hinman, Samantha B Draves, Stephanie A Matthews, Kristina A Simeone, Timothy A Simeone
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引用次数: 0

Abstract

The rate of sudden unexpected death in epilepsy (SUDEP) is ~1 per 1000 patients each year. Terminal events reportedly involve repeated and prolonged apnea, suggesting a failure to autoresuscitate. To better understand the mechanisms and identify novel therapeutics, standardized tests to screen for autoresuscitation efficacy are needed in preclinical SUDEP. To investigate the efficacy of the autoresuscitation response and potential contribution to SUDEP susceptibility, we adapted an anoxia-induced autoresuscitation test. The test was optimized to allow for survival of most wild-type (WT) mice, whereas autoresuscitation failure occurred for most Kcna1-/- mice, a preclinical model of SUDEP. Using whole-body plethysmography, we assessed ventilatory parameters, gasp-apnea dynamics, and survival in WT, Kcna1-/-, and Kcna1+/- mice. A proof-of-concept pharmacological rescue was performed using a dual orexin receptor antagonist (DORA). WT mice exhibited robust autoresuscitation (80% survival), whereas only 20% of high-risk Kcna1-/- mice survived the anoxic challenge, indicating a 4-fold increase in risk for autoresuscitation failure. Kcna1-/- mice had disordered ventilatory responses, characterized by increased minute ventilation, tidal volume, and expiratory flow during anoxia. Kcna1-/- mice initiated gasping earlier with reduced gasp number, lower gasp frequency, and longer post-gasp apnea durations. In-depth analyses revealed three phases of gasping. Phase III recovery gasping was significantly impaired in Kcna1-/- mice, and they were unable to transition to eupnea. In contrast, low-risk Kcna1-/- mice and Kcna1+/-mice showed intermediate to normal autoresuscitation, respectively. DORA pretreatment improved survival to 80%, restored ventilatory patterns, and normalized gasp-apnea metrics to WT levels. This modified autoresuscitation test provides a reproducible and sensitive approach to probe respiratory vulnerability in preclinical SUDEP models. Our findings identify augmented ventilatory chemosensitivity and impaired autoresuscitation as critical pathophysiological features of SUDEP in Kcna1-/- mice and support the utility of this test platform for preclinical therapeutic screening and mechanistic discovery.

临床前SUDEP模型的自动复苏测试的发展和特征。
癫痫猝死(SUDEP)的发生率每年约为千分之一。据报道,终末事件包括反复和延长的呼吸暂停,提示未能进行自动复苏。为了更好地了解机制和确定新的治疗方法,需要在临床前SUDEP中进行标准化测试以筛选自身复苏效果。为了研究自体复苏反应的有效性及其对SUDEP易感性的潜在贡献,我们采用了缺氧诱导的自体复苏试验。该测试经过优化,允许大多数野生型(WT)小鼠存活,而大多数Kcna1-/-小鼠(SUDEP的临床前模型)发生自动复苏失败。使用全身体积脉搏图,我们评估了WT、Kcna1-/-和Kcna1+/-小鼠的通气参数、喘息-呼吸动力学和生存率。使用双食欲素受体拮抗剂(DORA)进行概念验证的药理学拯救。WT小鼠表现出强大的自身复苏(80%存活率),而只有20%的高风险Kcna1-/-小鼠在缺氧挑战下存活,表明自身复苏失败的风险增加了4倍。Kcna1-/-小鼠有紊乱的通气反应,其特征是缺氧时的分钟通气量、潮气量和呼气流量增加。Kcna1-/-小鼠开始喘息较早,喘息次数减少,喘息频率降低,喘息后呼吸暂停持续时间延长。深入分析揭示了喘息的三个阶段。Kcna1-/-小鼠的III期恢复期喘息明显受损,无法过渡到呼吸暂停。相比之下,低风险Kcna1-/-小鼠和Kcna1+/-小鼠分别表现出中等至正常的自我复苏。DORA预处理将生存率提高到80%,恢复了通气模式,并将喘息-呼吸暂停指标正常化到WT水平。这种改进的自动复苏试验为临床前SUDEP模型的呼吸易感性提供了一种可重复和敏感的方法。我们的研究结果确定了Kcna1-/-小鼠SUDEP的关键病理生理特征是通气化学敏感性增强和自身复苏受损,并支持该测试平台用于临床前治疗筛选和机制发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Epilepsia
Epilepsia 医学-临床神经学
CiteScore
10.90
自引率
10.70%
发文量
319
审稿时长
2-4 weeks
期刊介绍: Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
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