A 5‐HT1D‐receptor agonist protects Dravet syndrome mice from seizure and early death,European Journal of Neuroscience

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A 5‐HT1D‐receptor agonist protects Dravet syndrome mice from seizure and early death
European Journal of Neuroscience ( IF 2.7 ) Pub Date : 2020-05-11 , DOI: 10.1111/ejn.14776
Paul G. Hatini _{1,

2} , Kathryn G. Commons _{1,

2}

Affiliation

Mutations in the SCN1A gene encoding the Nav1.1 sodium channel cause several forms of epilepsy, the most severe is Dravet syndrome (DS). DS patients are at high risk for sudden death and seizures are often triggered by fever or hyperthermia. To improve understanding of how serotonergic ligands might influence DS in this study, we tested several drugs for their effect on hyperthermia‐induced seizure using a mouse model of DS consisting of a heterozygous loss of function of Scn1A. We found that a mixed 5‐HT_2A/2C receptor agonist had no effect while a mixed 5‐HT_1B/D receptor agonist had a modest effect reducing the severity of seizures. Hypothesizing selective agonists may be more effective, we tested selective 5‐HT_1B and 5‐HT_1D receptor agonists, CP‐93129 and GR‐46611, respectively. Of these GR‐46611 significantly increased the threshold of hyperthermia‐induced seizure and lowered seizure severity. Given chronically at 1 mg kg⁻¹ day⁻¹, GR‐46611 also significantly improved survival of DS mice. Thus, 5‐HT_1D‐receptors may represent a meaningful target for pharmacotherapy for DS with potential relevance for related forms of epilepsy, particularly those with a known sensory trigger such as heat.

中文翻译：

5-HT1D-受体激动剂可保护Dravet综合征小鼠免于癫痫发作和早期死亡

编码Nav1.1钠通道的SCN1A基因中的突变会导致多种形式的癫痫，最严重的是Dravet综合征（DS）。DS患者极有可能突然死亡，癫痫发作通常是由发烧或体温过高引起的。为了在本研究中增进对血清素能配体如何影响DS的理解，我们使用由Scn1A功能杂合性缺失的DS小鼠模型测试了几种药物对热疗诱发的癫痫发作的作用。我们发现混合的5‐HT _{2A / 2C}受体激动剂无作用，而混合的5‐HT _{1B / D}受体激动剂对降低癫痫发作的严重程度有中等作用。假设性选择性激动剂可能更有效，我们测试了选择性5‐HT _1B和5‐HT_一维受体激动剂CP-93129和GR-46611。其中GR‐46611显着提高了热疗诱发的癫痫发作的阈值并降低了癫痫发作的严重程度。长期给予1 mg kg ^-1 天^-1的剂量，GR‐46611还可以显着提高DS小鼠的存活率。因此，5-HT _1D受体可能代表药物治疗DS的一个有意义的目标，与相关的癫痫形式有关，尤其是与已知的感觉触发因素如热有关的癫痫发作。

更新日期：2020-05-11

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