Evaluation of the efficacy of the hypocretin/orexin receptor agonists TAK-925 and ARN-776 in narcoleptic orexin/tTA; TetO-DTA mice.

Autor: Sun Y; Biosciences Division, SRI International, Menlo Park, California, USA., Ranjan A; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Tisdale R; Biosciences Division, SRI International, Menlo Park, California, USA., Ma SC; Biosciences Division, SRI International, Menlo Park, California, USA., Park S; Biosciences Division, SRI International, Menlo Park, California, USA., Haire M; Biosciences Division, SRI International, Menlo Park, California, USA., Heu J; Biosciences Division, SRI International, Menlo Park, California, USA., Morairty SR; Biosciences Division, SRI International, Menlo Park, California, USA., Wang X; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Rosenbaum DM; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.; Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Williams NS; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., De Brabander JK; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Kilduff TS; Biosciences Division, SRI International, Menlo Park, California, USA.
Jazyk: angličtina
Zdroj: Journal of sleep research [J Sleep Res] 2023 Aug; Vol. 32 (4), pp. e13839. Date of Electronic Publication: 2023 Feb 20.
DOI: 10.1111/jsr.13839
Abstrakt: 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 sc ) 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 sc , 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.
(© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)
Databáze: MEDLINE
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