Kommajosyula Srinivasa P, Tupal Srinivasan, Faingold Carl L
Departments of Pharmacology and Neurology, Southern Illinois University School of Medicine, PO BOX 19629, Springfield, IL, 62794-9629, United States.
Departments of Pharmacology and Neurology, Southern Illinois University School of Medicine, PO BOX 19629, Springfield, IL, 62794-9629, United States.
Epilepsy Res. 2018 Nov;147:1-8. doi: 10.1016/j.eplepsyres.2018.08.005. Epub 2018 Aug 19.
Post-ictal cardiorespiratory failure is implicated as a major cause of sudden unexpected death in epilepsy (SUDEP) in patients. The DBA/1 mouse model of SUDEP is abnormally susceptible to fatal seizure-induced cardiorespiratory failure (S-CRF) induced by convulsant drug, hyperthermia, electroshock, and acoustic stimulation. Clinical and pre-clinical studies have implicated periaqueductal gray (PAG) abnormalities in SUDEP. Recent functional neuroimaging studies observed that S-CRF resulted in selective changes in PAG neuronal activity in DBA/1 mice. The PAG plays a critical compensatory role for respiratory distress caused by numerous physiological challenges in non-epileptic individuals. These observations suggest that abnormalities in PAG-mediated cardiorespiratory modulation may contribute to S-CRF in DBA/1 mice. To evaluate this, electrical stimulation (20 Hz, 20-100 μA, 10 s) was presented in the PAG of anesthetized DBA/1 and C57BL/6 (non-epileptic) control mice, and post-stimulus changes in respiration [inter-breath interval (IBI)] and heart rate variability (HRV) were examined. The post-stimulus period was considered analogous to the post-ictal period when S-CRF occurred in previous DBA/1 mouse studies. PAG stimulation caused significant intensity-related decreases in IBI in both mouse strains. However, this effect was significantly reduced in DBA/1 vis-a-vis C57BL/6 mice. These changes began immediately following cessation of stimulation and remained significant for 10 s. This time period is critical for initiating resuscitation to successfully prevent seizure-induced death in previous DBA/1 mouse experiments. Significant post-stimulus increases in HRV were also seen at ≥60 μA in the PAG in C57BL/6 mice, which were absent in DBA/1 mice. These data along with previous neuroimaging findings suggest that compensatory cardiorespiratory modulation mediated by PAG is deficient, which may be important to the susceptibility of DBA/1 mice to S-CRF. These observations suggest that correcting this deficit pharmacologically or by electrical stimulation may help to prevent S-CRF. These findings further support the potential importance of PAG abnormalities to human SUDEP.
发作后心肺衰竭被认为是癫痫患者突然意外死亡（SUDEP）的主要原因。SUDEP的DBA/1小鼠模型异常易受惊厥药物、高热、电击和声刺激诱发的致命性癫痫发作诱导的心肺衰竭（S-CRF）影响。临床和临床前研究表明中脑导水管周围灰质（PAG）异常与SUDEP有关。最近的功能神经影像学研究观察到，S-CRF导致DBA/1小鼠PAG神经元活动发生选择性变化。在非癫痫个体中，PAG对多种生理挑战引起的呼吸窘迫起着关键的代偿作用。这些观察结果表明，PAG介导的心肺调节异常可能导致DBA/1小鼠发生S-CRF。为了评估这一点，对麻醉的DBA/1和C57BL/6（非癫痫）对照小鼠的PAG进行电刺激（20Hz，20 - 100μA，10s），并检查刺激后呼吸[呼吸间隔（IBI）]和心率变异性（HRV）的变化。刺激后时期被认为类似于先前DBA/1小鼠研究中发生S-CRF时的发作后期。PAG刺激在两种小鼠品系中均导致与强度相关的IBI显著降低。然而，与C57BL/6小鼠相比，DBA/1小鼠的这种效应明显减弱。这些变化在刺激停止后立即开始，并持续10s显著。在先前的DBA/1小鼠实验中，这段时间对于启动复苏以成功预防癫痫发作诱导的死亡至关重要。在C57BL/6小鼠的PAG中，≥60μA时刺激后HRV也有显著增加，而DBA/1小鼠中则没有。这些数据以及先前的神经影像学研究结果表明，PAG介导的代偿性心肺调节功能不足，这可能对DBA/1小鼠对S-CRF的易感性很重要。这些观察结果表明，通过药物或电刺激纠正这种缺陷可能有助于预防S-CRF。这些发现进一步支持了PAG异常对人类SUDEP的潜在重要性。
