Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality
Serotonin neurones have anti-convulsant effects and reduce seizure-induced mortality
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羟色胺神经元具有抗惊厥作用，可降低癫痫发作引起的死亡率
DOI：
10.1113/jphysiol.2014.277574
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发表时间：
2014-10-01
影响因子：
5.5
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
--
作者：
Buchanan, Gordon F.;Murray, Nicholas M.;Richerson, George B.
癫痫猝死（SUDEP）是难治性癫痫患者死亡的主要原因。呼吸中枢控制缺陷是SUDEP病理生理的重要因素，5-羟色胺（5-HT）系统功能障碍可能参与其中。在这里，我们研究了5-HT神经元消除或5-HT减少对癫痫发作风险和癫痫引起的死亡率的影响。成年Lmx1b（f/f/p）小鼠在中枢神经系统中缺乏> - 99%的5-HT神经元，与同鼠对照（Lmx1b(f/f)）进行最大电休克（MES）或匹罗卡平诱导急性癫痫发作，包括脑电图、心电图、容积描图、机械通气或药物治疗。Lmx1b（f/f/p）小鼠癫痫发作阈值较低，癫痫引起的死亡率升高。在大多数癫痫发作期间呼吸停止而无恢复，而心脏活动在终末期骤停前持续长达9分钟。癫痫发作时机械通气或5-HT2A受体激动剂预处理均可降低两种基因型小鼠的死亡率。选择性5 -羟色胺再摄取抑制剂西酞普兰降低了Lmx1b（f/f）小鼠的死亡率，但对Lmx1b（f/f/p）小鼠没有作用。在C57BL/6N小鼠中，用对氯苯丙氨酸减少5-HT合成增加mes诱导的癫痫发作严重程度，但不增加死亡率。我们得出结论，5-HT神经元提高癫痫阈值，降低癫痫相关死亡率。患者死于呼吸衰竭，随后是终末期心脏骤停。鉴于SUDEP通常与全身性癫痫发作相关，我们的模型中导致死亡的一些机制可能与导致SUDEP的机制相同。该模型可能有助于确定癫痫发作、5-羟色胺系统功能障碍、呼吸和死亡之间的关系，从而可能找到预防SUDEP的新方法。
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Defects in central control of breathing are important contributors to the pathophysiology of SUDEP, and serotonin (5-HT) system dysfunction may be involved. Here we examined the effect of 5-HT neurone elimination or 5-HT reduction on seizure risk and seizure-induced mortality. Adult Lmx1b(f/f/p) mice, which lack >99% of 5-HT neurones in the CNS, and littermate controls (Lmx1b(f/f)) were subjected to acute seizure induction by maximal electroshock (MES) or pilocarpine, variably including electroencephalography, electrocardiography, plethysmography, mechanical ventilation or pharmacological therapy. Lmx1b(f/f/p) mice had a lower seizure threshold and increased seizure-induced mortality. Breathing ceased during most seizures without recovery, whereas cardiac activity persisted for up to 9 min before terminal arrest. The mortality rate of mice of both genotypes was reduced by mechanical ventilation during the seizure or 5-HT2A receptor agonist pretreatment. The selective serotonin reuptake inhibitor citalopram reduced mortality of Lmx1b(f/f) but not of Lmx1b(f/f/p) mice. In C57BL/6N mice, reduction of 5-HT synthesis with para-chlorophenylalanine increased MES-induced seizure severity but not mortality. We conclude that 5-HT neurones raise seizure threshold and decrease seizure-related mortality. Death ensued from respiratory failure, followed by terminal asystole. Given that SUDEP often occurs in association with generalised seizures, some mechanisms causing death in our model might be shared with those leading to SUDEP. This model may help determine the relationship between seizures, 5-HT system dysfunction, breathing and death, which may lead to novel ways to prevent SUDEP.