@article{724a6481423e4ae3a6a77f55969be6ca,
title = "Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway",
abstract = "Thalidomide exerts its teratogenic and immunomodulatory effects by binding to cereblon (CRBN) and thereby inhibiting/modifying the CRBN-mediated ubiquitination pathway consisting of the Cullin4-DDB1-ROC1 E3 ligase complex. The mechanism of thalidomide{\textquoteright}s classical hypnotic effect remains largely unexplored, however. Here we examined whether CRBN is involved in the hypnotic effect of thalidomide by generating mice harboring a thalidomide-resistant mutant allele of Crbn (Crbn YW/AA knock-in mice). Thalidomide increased non-REM sleep time in Crbn YW/AA knock-in homozygotes and heterozygotes to a similar degree as seen in wild-type littermates. Thalidomide similarly depressed excitatory synaptic transmission in the cortical slices obtained from wild-type and Crbn YW/AA homozygous knock-in mice without affecting GABAergic inhibition. Thalidomide induced Fos expression in vasopressin-containing neurons of the supraoptic nucleus and reduced Fos expression in the tuberomammillary nuclei. Thus, thalidomide{\textquoteright}s hypnotic effect seems to share some downstream mechanisms with general anesthetics and GABAA-activating sedatives but does not involve the teratogenic CRBN-mediated ubiquitin/proteasome pathway.",
author = "Yuki Hirose and Tomohiro Kitazono and Maiko Sezaki and Manabu Abe and Kenji Sakimura and Hiromasa Funato and Hiroshi Handa and Vogt, {Kaspar E.} and Masashi Yanagisawa",
note = "Funding Information: ACKNOWLEDGMENTS. We thank T. Kanbayashi for information on thalidomide in vivo experiments and T. Chiba for technical advice regarding the ubiquitination assay. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology (26220207, 15H05935, and 17H06095, to M.Y.), the Japan Science and Technology Agency{\textquoteright}s Core Research for Evolutional Science and Technology program (A3A28043, to M.Y.), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Japan Society for the Promotion of Science (JSPS) (to M.Y.), a World Premier International Research Center Initiative from the JSPS (to M.Y.), a research grant from the Uehara Memorial Foundation (to M.Y.), and a research grant from the Takeda Science Foundation (to M.Y.). Funding Information: We thank T. Kanbayashi for information on thalidomide in vivo experiments and T. Chiba for technical advice regarding the ubiquitination assay. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology (26220207, 15H05935, and 17H06095, to M.Y.), the Japan Science and Technology Agency?s Core Research for Evolutional Science and Technology program (A3A28043, to M.Y.), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Japan Society for the Promotion of Science (JSPS) (to M.Y.), a World Premier International Research Center Initiative from the JSPS (to M.Y.), a research grant from the Uehara Memorial Foundation (to M.Y.), and a research grant from the Takeda Science Foundation (to M.Y.). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = sep,
day = "15",
doi = "10.1073/pnas.1917701117",
language = "English (US)",
volume = "117",
pages = "23106--23112",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "37",
}