Susceptibility to seizure-induced sudden death in DBA/2 mice is altered by adenosine
Susceptibility to seizure-induced sudden death in DBA/2 mice is altered by adenosine
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DOI：
10.1016/j.eplepsyres.2016.05.007
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发表时间：
2016-08-01
影响因子：
2.2
通讯作者：
Kommajosyula, Srinivasa P.
中科院分区：
文献类型：
--
作者：
Faingold, Carl L.;Randall, Marc;Kommajosyula, Srinivasa P.
癫痫猝死（SUDEP）是罕见的，但由于患者年数的损失，是一个重要的公共卫生负担。全身性惊厥发作后的呼吸功能障碍是SUDEP病例中常见的事件序列。DBA/2小鼠SUDEP模型表现为全身性惊厥性听源性癫痫发作（AGSz），在75%的小鼠中导致癫痫诱发呼吸骤停（S-IRA），而其余DBA/2小鼠表现为AGSz，没有S-IRA。猝死症的诱导可能涉及腺苷的作用，腺苷在动物和患者全身性癫痫发作时释放，已知可抑制呼吸。本研究检查了全身给药改变腺苷作用的药物对DBA/2小鼠S-IRA发病率的影响。持续表现AGSz而不表现S-IRA的DBA/2小鼠在5-碘结核菌素治疗后，S-IRA的发生率显著增加，5-碘结核菌素阻断腺苷代谢。用非选择性腺苷拮抗剂、咖啡因或A2(a)腺苷受体亚型选择性拮抗剂（SCH 442416）治疗一贯表现出AGSz的DBA/2小鼠，可显著降低S-IRA的发病率。相比之下，A1腺苷受体拮抗剂（DPCPX）在降低S-IRA发生率方面没有效果。这些发现表明，预防SUDEP的方法应该考虑降低腺苷作用的药物。(C) 2016 Elsevier B.V.版权所有
Sudden unexpected death in epilepsy (SUDEP) is rare but is an important public health burden due to the number of patient years lost. Respiratory dysfunction following generalized convulsive seizure is a common sequence of events in witnessed SUDEP cases. The DBA/2 mouse model of SUDEP exhibits generalized convulsive audiogenic seizures (AGSz), which result in seizure-induced respiratory arrest (S-IRA) in similar to 75% of these animals, while the remaining DBA/2 mice exhibit AGSz without S-IRA. SUDEP induction may involve actions of adenosine, which is released during generalized seizures in animals and patients and is known to depress respiration. This study examined the effects of systemic administration of agents that alter the actions of adenosine on the incidence of S-IRA in DBA/2 mice. DBA/2 mice that consistently exhibited AGSz without S-IRA showed a significantly increased incidence of S-IRA following treatment with 5-iodotubercidin, which blocks adenosine metabolism. Treatment of DBA/2 mice that consistently exhibited AGSz followed by S-IRA with a non-selective adenosine antagonist, caffeine, or an A2(A) adenosine receptor subtype-selective antagonist (SCH 442416) significantly reduced S-IRA incidence. By contrast, an A1 adenosine receptor antagonist (DPCPX) was not effective in reducing S-IRA incidence. These findings suggest that preventative approaches for SUDEP should consider agents that reduce the actions of adenosine. (C) 2016 Elsevier B.V. All rights reserved.