Glucocorticoids get Smoothened

Lou, Kai-Jye

doi:10.1038/scibx.2010.607

Cited by 1 publication

(1 citation statement)

References 3 publications

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“…It should be mentioned also that synthetic Smo agonists are under observation for safety issues, since activating mutations of Smo are associated with the development of multiple type of cancers [ 67 ]. However, the safety profile of Clobetasol and Halcinonide has been known for decades, so such an issue cannot be applied to these specific Smo agonists [ 68 ]. Dexamethasone is one of the most widely used corticosteroids for the management of acute MS exacerbations due to its ability to reduce CNS inflammation and close the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Clobetasol and Halcinonide Act as Smoothened Agonists to Promote Myelin Gene Expression and RxRγ Receptor Activation

et al. 2015

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One of the causes of permanent disability in chronic multiple sclerosis patients is the inability of oligodendrocyte progenitor cells (OPCs) to terminate their maturation program at lesions. To identify key regulators of myelin gene expression acting at the last stages of OPC maturation we developed a drug repositioning strategy based on the mouse immortalized oligodendrocyte (OL) cell line Oli-neu brought to the premyelination stage by stably expressing a key factor regulating the last stages of OL maturation. The Prestwick Chemical Library® of 1,200 FDA-approved compound(s) was repositioned at three dosages based on the induction of Myelin Basic Protein (MBP) expression. Drug hits were further validated using dosage-dependent reproducibility tests and biochemical assays. The glucocorticoid class of compounds was the most highly represented and we found that they can be divided in three groups according to their efficacy on MBP up-regulation. Since target identification is crucial before bringing compounds to the clinic, we searched for common targets of the primary screen hits based on their known chemical-target interactomes, and the pathways predicted by top ranking compounds were validated using specific inhibitors. Two of the top ranking compounds, Halcinonide and Clobetasol, act as Smoothened (Smo) agonists to up-regulate myelin gene expression in the Oli-neuM cell line. Further, RxRγ activation is required for MBP expression upon Halcinonide and Clobetasol treatment. These data indicate Clobetasol and Halcinonide as potential promyelinating drugs and also provide a mechanistic understanding of their mode of action in the pathway leading to myelination in OPCs. Furthermore, our classification of glucocorticoids with respect to MBP expression provides important novel insights into their effects in the CNS and a rational criteria for their choice in combinatorial therapies in de-myelinating diseases.

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Section: Discussionmentioning

confidence: 99%