Abstract:
Because of its involvement in breathing control and neuronal excitability, dysregulation of the serotonin (5-HT) 2C receptor (5-HT2C) might play a key role in sudden unexpected death in epilepsy. Seizure-induced respiratory arrest is thus prevented by a 5-HT2B/C agonist in different seizure model. However, the specific contribution of 5-HT2C in chronic epilepsy-related respiratory dysfunction remains unknown. In a rat model of temporal lobe epilepsy (EPI rats), in which we previously reported interictal respiratory dysfunctions and a reduction of brainstem 5-HT tone, quantitative reverse transcriptase polymerase chain reaction showed overexpression of TPH2 (5-HT synthesis enzyme), SERT (5-HT reuptake transporter), and 5-HT2C transcript levels in the brainstem of EPI rats, and of RNA-specific adenosine deaminase (ADAR1, ADAR2) involved in the production of 5-HT2C isoforms. Interictal ventilation was assessed with whole-body plethysmography before and 2 h after administration of SB242084 (2 mg/kg), a specific antagonist of 5-HT2C. As expected, SB242084 administration induced a progressive decrease in ventilatory parameters and an alteration of breathing stability in both control and EPI rats. However, the size of the SB242084 effect was lower in EPI rats than in controls. Increased 5-HT2C gene expression in the brainstem of EPI rats could be part of a compensatory mechanism against epilepsy-related low 5-HT tone and expression of 5-HT2C isoforms for which 5-HT affinity might be lower.
摘要:
因为它参与呼吸控制和神经元兴奋性,5-羟色胺(5-HT)2C受体(5-HT2C)的失调可能在癫痫猝死中起关键作用。因此,在不同的癫痫发作模型中,5-HT2B/C激动剂可以防止癫痫发作引起的呼吸停止。然而,5-HT2C在慢性癫痫相关呼吸功能障碍中的具体作用尚不清楚.在颞叶癫痫大鼠模型(EPI大鼠)中,其中我们先前报道了发作间呼吸功能障碍和脑干5-HT音调降低,定量逆转录聚合酶链反应显示TPH2(5-HT合成酶)过表达,SERT(5-HT再摄取转运蛋白),和EPI大鼠脑干中的5-HT2C转录物水平,以及参与5-HT2C亚型产生的RNA特异性腺苷脱氨酶(ADAR1,ADAR2)。在给予SB242084(2mg/kg)之前和之后2小时,用全身体积描记术评估发作间通气,5-HT2C的特异性拮抗剂。不出所料,SB242084给药在对照和EPI大鼠中均引起通气参数的进行性降低和呼吸稳定性的改变。然而,EPI大鼠的SB242084效应的大小低于对照组。EPI大鼠脑干中5-HT2C基因表达的增加可能是针对癫痫相关的低5-HT音调和5-HT2C同工型表达的代偿机制的一部分,其中5-HT亲和力可能较低。