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.
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Barrat et al. found that all metabolites of tamoxifen (4-hydroxytamoxifen and endoxifen) as well as tamoxifen citrate promoted expression of late stage markers of OPC differentiation such as Cnp and Mbp.
“They found that all metabolites promoted the expression of late stage markers of OPC differentiation, such as Cnp and Mbp, which is consistent with our findings using primary rat OPC cultures.”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [43]
The effect of tamoxifen was blocked when a pan-antagonist was added to the media, supporting that tamoxifen acts as an estrogen receptor agonist in OPC differentiation.
“In addition, the effect of tamoxifen was blocked when a pan-antagonist was added to the media, supporting our finding that tamoxifen acts as an estrogen receptor agonist in OPC differentiation.”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [43]
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Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system
Gonzalez, G. A., Hofer, M. P., Syed, Y. A., Amaral, A. I., Rundle, J., Rahman, S., Zhao, C., & Kotter, M. R. N. (2016) · Scientific Reports · doi:10.1038/srep31599 · Cited by 82 · see citing works
“However, a recent paper by Barrat et al. evaluated metabolites of tamoxifen (4-hydroxytamoxifen and endoxifen) as well as tamoxifen citrate, a water-soluble version on a rat glia restricted precursor cell line 43 .”
Background
- Authors
- Barratt, H. E., Budnick, H. C., Parra, R., Lolley, R. J., Perry, C. N., & Nesic, O.
- Affiliations
- Texas Tech University Health Sciences Center (US)
- Virginia Tech (US)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 319
- Pages
- 146-154
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2251362463
- Cited by
- 22
- References
- 56
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- eCommons - AKU (Aga Khan University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- tamoxifen, oligodendrocyte precursor cells, oligodendrocyte differentiation, demyelinating disease, estrogen receptor, tamoxifen citrate, 4-hydroxytamoxifen, endoxifen, astrogliogenesis, myelin basic protein, CNPase, drug repurposing
- MeSH terms
- Animals, Cell Differentiation, Fluorescent Antibody Technique, Oligodendroglia, Prodrugs, Tamoxifen, Blotting, Western, Rats, Neural Stem Cells
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