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Contributed by Masashi Yanagisawa, July 19, 2020 (sent for review October 10, 2019; reviewed by Ying-Hui Fu and Toru Takumi)
Significance
Thalidomide was introduced in 1950s as a safe and effective hypnotic but was subsequently withdrawn from the market due to its devastating teratogenicity in humans. More recently, thalidomide has reemerged as an antineoplastic and immunomodulatory medicine. The teratogenic and immunomodulatory effects of thalidomide have been attributed to direct inhibition of the cereblon-mediated ubiquitin/proteasome pathway. Here we show that cereblon is not involved in the hypnotic effect of thalidomide, using mice that carry a thalidomide-resistant mutant allele of the cereblon gene. Our results suggest the possibility for dissociating the hypnotic effect of thalidomide and its analogs from its teratogenicity.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: yanagisawa.masa.fu{at}u.tsukuba.ac.jp.
Author contributions: Y.H., H.F., K.E.V., and M.Y. designed research; Y.H., T.K., and M.S. performed research; M.A., K.S., and H.H. contributed new reagents/analytic tools; Y.H. and T.K. analyzed data; and Y.H., K.E.V., and M.Y. wrote the paper.
Reviewers: Y.-H.F., University of California, San Francisco; and T.T., RIKEN.
The authors declare no competing interest.
Data Availability.
All study data are included in the main text.
Published under the PNAS license.
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Hypnotic effect of thalidomide is independent of teratogenic ubiquitin/proteasome pathway
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