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过早死亡。

编码 Nav1.1 钠通道的 SCN1A 基因突变会导致多种形式的癫痫，最严重的是 Dravet 综合征 (DS)。DS 患者猝死的风险很高，癫痫发作通常由发烧或体温过高引起。为了加深对本研究中血清素配体如何影响 DS 的理解，我们使用由Scn1A杂合功能丧失组成的 DS 小鼠模型测试了几种药物对热疗诱发癫痫发作的影响。我们发现混合的 5-HT _2A/2C受体激动剂没有效果，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适度的作用。假设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，分别是 CP-93129 和 GR-46611。其中 GR-46611 显着增加了热疗诱发癫痫发作的阈值并降低了癫痫发作的严重程度。长期以 1 mg kg ^-1 天^-1给药，GR-46611 也显着提高了 DS 小鼠的存活率。因此，5-HT _1D受体可能是 DS 药物治疗的一个有意义的靶点，与相关形式的癫痫（特别是那些具有已知感觉触发因素（如热）的癫痫）具有潜在相关性。

更新日期：2020-05-11

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