Fig. 3 | Scientific Reports

Fig. 3

From: TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models

Fig. 3

Effects of TAK-861 on narcolepsy-like symptoms in orexin/ataxin-3 mice during the active phase. (a) Time schedule of drug administration in orexin/ataxin-3 mice during the active phase for evaluation for sleep/wakefulness states. TAK-861 or vehicle was administered orally to mice at ZT12, and then EEG/EMG and locomotor activity were recorded. (b) Representative hypnogram for 3 h after TAK-861 (1 mg/kg) or vehicle administration in orexin/ataxin-3 mice. (c) Effect of TAK-861 (0.1, 0.3, and 1 mg/kg) on wakefulness time in 10-min bins for 3 h (left) and total wakefulness time for 1 h (right) after administration in orexin/ataxin-3 mice. Effect of TAK-861 (0.1, 0.3, and 1 mg/kg) on (d) number of wakefulness episode and (e) mean duration of wakefulness episode for 1 h after administration in orexin/ataxin-3 mice. Mean ± SEM; n = 8. **p < 0.01, ***p < 0.001, compared with vehicle-treated mice, as determined by two-tailed Shirley-Williams test. (f) Time schedule of drug administration in orexin/ataxin-3 mice during the active phase for evaluation of cataplexy-like episodes. After drug administration, chocolate was placed in the cage. The number of cataplexy-like episodes was determined for 3 h after administration. (g) Effect of TAK-861 (0.1, 0.3, and 1 mg/kg) on cataplexy-like episodes in orexin/ataxin-3 mice. Mean ± SEM; n = 8. **p < 0.01, compared with vehicle-treated mice, as determined by two-tailed Shirley-Williams test. (h) Time schedule of repeated drug administration in mice during the active phase. In the control or sub-chronic treatment group, vehicle or TAK-861 was orally administered to mice at ZT12 for 14 days, respectively. In the acute treatment group, vehicle was orally administered to mice at ZT12 for 13 days then TAK-861 was administrated on day 14. (i) Effects of acute and sub-chronic treatment of TAK-861 (1 mg/kg) on wakefulness time in 1-h bins for 12 h (left) and total wakefulness time for 1 h (right) after administration in orexin/ataxin-3 mice. Mean ± SEM; n = 8. ***p < 0.001, compared with vehicle-treated mice, as determined by Tukey’s multiple comparison test. n.s. not significant, EEG electroencephalogram, EMG electromyogram, SEM standard error of the mean, ZT zeitgeber time.

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