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’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.

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders

“…It should be cautioned, however, that, whereas, the anti-inflammatory actions of IMiDs clearly involve cereblon-dependent and -independent mechanisms, so too may pathways that underpin teratogenic, anticancer, and anti-angiogenic actions. Indeed, cereblon-independent anti-angiogenic IMiD actions have been reported [73], and the hypnotic effects of thalidomide likewise appear to be independent of cereblon [150]. Other proteins, in addition to SALL4, such as the tumor protein p63 that has multiple isoforms, the major of which are TAP63 and ∆NP63, are subject to thalidomide-mediated degradation and appear to be involved in different teratogenic phenotypes [151].…”

Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders

“…53 Concordantly, the (S)-enantiomer exhibits about 10-fold stronger binding to CRBN, 54 whereas the hypnotic effect of thalidomide is reportedly CRBN-independent. 55 Recent findings have improved our understanding of the molecular mechanisms of thalidomide embryopathy. In 2018, two independent groups reported Spalt-like transcription factor 4 (SALL4) as a neosubstrate involved in the teratogenicity of thalidomide.…”

“…53 Concordantly, the ( S )-enantiomer exhibits about 10-fold stronger binding to CRBN, 54 whereas the hypnotic effect of thalidomide is reportedly CRBN-independent. 55…”

Identifying c-fos Expression as a Strategy to Investigate the Actions of General Anesthetics on the Central Nervous System

“…Very few studies have explored the function of SON in sleep-wakefulness regulation; however, the number of damaged cells was increased in the SON after severe sleep deprivation [ 43 ]. Recently, it was reported that the hypnotic effect of thalidomide, a nonbarbiturate hypnotic agent, may be associated with the activation of vasopressin-containing neurons in SON due to the significantly increased c-fos expression [ 45 ]. Interestingly, a recent study reported that SON neurons are commonly activated by various classes of general anesthetics, including isoflurane (1%-1.2%), propofol (180 mg/kg), ketamine (100 mg/kg), and dexmedetomidine (100 μg/kg) determined by increased c-fos expression, recording of brain slices, and in vivo recording of multichannel electrophysiology [ 18 ].…”