Pharmacological Targeting the REV-ERBs in Sleep/Wake Regulation.
The circadian clock maintains appropriate timing for a wide range of behaviors and physiological processes. Circadian behaviors such as sleep and wakefulness are intrinsically dependent on the precise oscillation of the endogenous molecular machinery that regulates the circadian clock. The identical core clock machinery regulates myriad endocrine and metabolic functions providing a link between sleep and metabolic health. The REV-ERBs (REV-ERBα and REV-ERBβ) are nuclear receptors that are key regulators of the molecular clock and have been successfully targeted using small molecule ligands. Recent studies in mice suggest that REV-ERB-specific synthetic agonists modulate metabolic activity as well as alter sleep architecture, inducing wakefulness during the light period. Therefore, these small molecules represent unique tools to extensively study REV-ERB regulation of sleep and wakefulness. In these studies, our aim was to further investigate the therapeutic potential of targeting the REV-ERBs for regulation of sleep by characterizing efficacy, and optimal dosing time of the REV-ERB agonist SR9009 using electroencephalographic (EEG) recordings. Applying different experimental paradigms in mice, our studies establish that SR9009 does not lose efficacy when administered more than once a day, nor does tolerance develop when administered once a day over a three-day dosing regimen. Moreover, through use of a time response paradigm, we determined that although there is an optimal time for administration of SR9009 in terms of maximal efficacy, there is a 12-hour window in which SR9009 elicited a response. Our studies indicate that the REV-ERBs are potential therapeutic targets for treating sleep problems as those encountered as a consequence of shift work or jet lag.
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, 34583, United States of America.
Ariadna
A
Amador
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, 92037, United States of America.
Salvador
S
Huitron-Resendiz
Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California, 92037, United States of America.
Amanda J
AJ
Roberts
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, 34583, United States of America.
Theodore M
TM
Kamenecka
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida, 34583, United States of America.
Laura A
LA
Solt
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, 63104, United States of America.
Thomas P
TP
Burris
D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects; D004569:Electroencephalography; D008027:Light; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists / Q000378:metabolism*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D012895:Sleep, REM / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*
D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011759:Pyrrolidines; C572451:SR9009; D013876:Thiophenes