Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway

Yuki Hirose, Tomohiro Kitazono, Maiko Sezaki, Manabu Abe, Kenji Sakimura, Hiromasa Funato, Hiroshi Handa, Kaspar E. Vogt, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

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’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’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.

Original languageEnglish (US)
Pages (from-to)23106-23112
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number37
DOIs
StatePublished - Sep 15 2020

ASJC Scopus subject areas

  • General

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