Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics.
Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics.
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DOI：
10.1016/j.biopsych.2016.10.012
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发表时间：
2017-11-01
影响因子：
10.6
通讯作者：
Kilduff TS
中科院分区：
文献类型：
--
作者：
Black SW;Schwartz MD;Chen TM;Hoener MC;Kilduff TS
发作性睡病是一种快速眼动（REM）睡眠障碍，其特征是白天过度嗜睡和紧张症，即由情绪刺激引发的肌肉张力丧失。目前的嗜睡症药物治疗包括具有滥用潜力的受控物质或具有不良副作用的药物。由于微量胺相关受体1（TAAR 1）的部分激动剂促进小鼠和大鼠的觉醒，我们评估了TAAR 1激动剂是否在两种发作性睡病小鼠模型中具有有益作用。在第一个实验中，通过手术植入雄性纯合B6-Taar 1 tm 1（NLSLacZ）Blt（Taar 1 KO）和野生型小鼠，以记录EEG、EMG、自发活动（LMA）和体温（Tb），并确定TAAR 1激动剂RO 5256390对睡眠/觉醒和生理参数的疗效。在第二个实验中，在两种小鼠发作性睡病模型中评估了TAAR 1完全激动剂R 0 5256390和部分激动剂R 0 5263397对睡眠/觉醒、LMA、Tb和紧张症的影响。RO 5256390显著减少野生型小鼠的REM睡眠;这些作用在Taar 1 KO小鼠中消除。TAAR 1部分激动剂RO 5263397也促进觉醒并抑制NREM睡眠。两种化合物在最高测试剂量下降低了两种嗜睡症模型中的Tb。两种TAAR 1化合物还减轻了小鼠发作性睡病模型中的cataerosis，即这种疾病的特征性症状。治疗获益是通过减少紧张性发作次数和紧张性发作时间介导的。这些结果表明TAAR 1激动作为治疗这种孤儿疾病的新的治疗途径。共同的潜在机制可能是抑制REM睡眠。
Narcolepsy, a disorder of Rapid Eye Movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. Since partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy. In the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt (Taar1 KO) and wildtype mice were surgically implanted to record EEG, EMG, locomotor activity (LMA) and body temperature (Tb) and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, LMA, Tb and cataplexy were assessed in two mouse narcolepsy models. RO5256390 profoundly reduced REM sleep in wildtype mice; these effects were eliminated in Taar1 KO mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed NREM sleep. Both compounds reduced Tb in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the mouse narcolepsy models. The therapeutic benefit was mediated through a reduction in the number of cataplexy episodes and time spent in cataplexy. These results suggest TAAR1 agonism as a new therapeutic pathway for the treatment of this orphan disease. The common underlying mechanism may be the suppression of REM sleep.