Biosciences Division, SRI International, Menlo Park, California, USA.
Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
J Sleep Res. 2023 Aug;32(4):e13839. doi: 10.1111/jsr.13839. Epub 2023 Feb 20.
The sleep disorder narcolepsy, a hypocretin deficiency disorder thought to be due to degeneration of hypothalamic hypocretin/orexin neurons, is currently treated symptomatically. We evaluated the efficacy of two small molecule hypocretin/orexin receptor-2 (HCRTR2) agonists in narcoleptic male orexin/tTA; TetO-DTA mice. TAK-925 (1-10 mg/kg, s.c.) and ARN-776 (1-10 mg/kg, i.p.) were injected 15 min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (T ) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep/wake and cataplexy. At all doses tested, TAK-925 and ARN-776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK-925 and ARN-776 caused dose-related delays in NREM sleep onset. All doses of TAK-925 and all but the lowest dose of ARN-776 eliminated cataplexy during the first hour after treatment; the anti-cataplectic effect of TAK-925 persisted into the second hour for the highest dose. TAK-925 and ARN-776 also reduced the cumulative amount of cataplexy during the 6 h post-dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post-dosing. TAK-925 and ARN-776 also increased gross motor activity, running wheel activity, and T , suggesting that the wake-promoting and sleep-suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti-cataplectic activity of TAK-925 and ARN-776 is encouraging for the development of HCRTR2 agonists.
发作性睡病是一种下丘脑分泌素/食欲素神经元退化导致的下丘脑分泌素/食欲素缺乏症，目前主要采用对症治疗。我们评估了两种小分子食欲素/orexin 受体-2（HCRTR2）激动剂在男性发作性睡病 Orexin/tTA； TetO-DTA 小鼠中的疗效。TAK-925（1-10mg/kg，皮下注射）和 ARN-776（1-10mg/kg，腹腔注射）在黑暗开始前 15 分钟以重复测量设计进行注射。通过遥测记录脑电图、肌电图、皮下温度（T）和活动；黑暗期前 6 小时的记录用于睡眠/觉醒和猝倒评分。在所有测试剂量下，TAK-925 和 ARN-776 均导致持续觉醒并在第一小时消除睡眠。TAK-925 和 ARN-776 均引起非快速眼动睡眠起始的剂量相关延迟。TAK-925 的所有剂量和 ARN-776 的除最低剂量外，均在治疗后第一小时消除猝倒；TAK-925 的抗猝倒作用在最高剂量时持续到第二个小时。TAK-925 和 ARN-776 还减少了 6 小时给药后累积的猝倒量。两种 HCRTR2 激动剂引起的急性觉醒增加，其特征是脑电图伽马频段的谱功率增加。虽然这两种化合物都没有引起非快速眼动睡眠反弹，但这两种化合物在给药后第二个小时都影响了非快速眼动脑电图。TAK-925 和 ARN-776 还增加了总体运动活动、跑步轮活动和 T，表明这些化合物的促觉醒和睡眠抑制活动可能是过度活跃的结果。尽管如此，TAK-925 和 ARN-776 的抗猝倒活性令人鼓舞，为 HCRTR2 激动剂的发展提供了希望。
