title: Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro.
abstract: The most promising therapeutic approach to finding the cure for devastating demyelinating conditions is the identification of clinically safe pharmacological agents that can promote differentiation of endogenous oligodendrocyte precursor cells (OPCs). Here we show that the breast cancer medication tamoxifen (TMX), with well-documented clinical safety and confirmed beneficial effects in various models of demyelinating conditions, stimulates differentiation of rat glial progenitors to mature oligodendrocytes in vitro. Clinically applicable doses of TMX significantly increased both the number of CNPase-positive oligodendrocytes and protein levels of myelin basic protein, measured with Western blots. Furthermore, we also found that OPC differentiation was stimulated, not only by the pro-drug TMX-citrate (TMXC), but also by two main TMX metabolites, 4-hydroxy-TMX and endoxifen. Differentiating effects of TMXC and its metabolites were completely abolished in the presence of estrogen receptor (ER) antagonist, ICI182780. In contrast to TMXC and 4-hydroxy-TMX, endoxifen also induced astrogliogenesis, but independent of the ER activation. In sum, we showed that the TMX prodrug and its two main metabolites (4-hydroxy-TMX and endoxifen) promote ER-dependent oligodendrogenesis in vitro, not reported before. Given that differentiating effects of TMX were achieved with clinically safe doses, TMX is likely one of the most promising FDA-approved drugs for the possible treatment of demyelinating diseases.
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States.
authors.forename: H E
authors.initials: HE
authors.lastname: Barratt
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States.
authors.forename: H C
authors.initials: HC
authors.lastname: Budnick
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States.
authors.forename: R
authors.initials: R
authors.lastname: Parra
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lolley
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States.
authors.forename: C N
authors.initials: CN
authors.lastname: Perry
authors.affiliation: Department of Medical Education, Texas Tech University Health Sciences Center El Paso: Paul L. Foster School of Medicine, United States; Department of Biomedical Sciences, Virginia Tech Carilion School of Medicine; Virginia Tech Carilion Research Institute, Roanoke, VA 24016, United States. Electronic address: olnesic@vt.edu.
authors.forename: O
authors.initials: O
authors.lastname: Nesic
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D011355:Prodrugs / Q000494:pharmacology; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D011355:Prodrugs; D013629:Tamoxifen
keywords: 4-hydroxy-tamoxifen; astrocytes; endoxifen; estrogen receptors; oligodendrocyte progenitors; tamoxifen