Abnormalities of serotonergic neurotransmission in animal models of SUDEP.
Abnormalities of serotonergic neurotransmission in animal models of SUDEP.
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DOI：
10.1016/j.yebeh.2015.06.008
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Faingold CL
中科院分区：
文献类型：
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作者：
Feng HJ;Faingold CL
癫痫猝死（Sudden unexpected death in epilepsy，SUDEP）是一种毁灭性的疾病，DBA/1和DBA/2小鼠是研究SUDEP的理想动物模型。DBA小鼠表现出惊厥诱导的呼吸骤停（S-IRA），导致心脏骤停和随后的全身性听源性癫痫发作（AGS）后的猝死。在大多数目击的人类SUDEP病例中也观察到了这种终末事件序列。已经提出了几种病理生理机制，包括呼吸/心脏功能障碍，有助于人类SUDEP。包括氟西汀在内的几种（但不是全部）选择性5-羟色胺（5-HT）再摄取抑制剂（SSRIs）可可逆地阻断S-IRA，DBA小鼠脑干中发现5-HT受体的异常表达。DBA小鼠最初不显示S-IRA，但在用非选择性5-HT拮抗剂治疗后显示S-IRA。这些研究提示DBA小鼠S-IRA的发病机制可能与5-HT神经传递异常有关。5-HT传递在正常呼吸中起重要作用，并且表现出S-IRA的DBA小鼠可以使用啮齿动物呼吸机复苏。氟西汀是否通过增强DBA小鼠的呼吸功能而阻断S-IRA是一个重要而有趣的研究课题。为了测试这一点，将呼吸兴奋剂多沙普仑和5，6，7，8-四氢吡啶并[4，3-d]嘧啶（PK-THPP）对DBA/1小鼠中S-IRA的作用与氟西汀进行比较。尽管氟西汀降低了DBA/1小鼠中S-IRA的发生率，如先前所报道的，但在不存在AGS的情况下，相同剂量的氟西汀未能增强基线呼吸通气。多沙普仑和PK-THPP增加DBA/1小鼠的基线通气。然而，这些呼吸兴奋剂在DBA/1小鼠中预防S-IRA是无效的。这些数据表明，氟西汀阻断DBA/1小鼠的S-IRA的细胞/分子机制，而不是增强基础通气。最后对今后的研究方向进行了展望。
Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGS). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a non-selective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. 5-HT transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared to fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGS. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed.