Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER) α and ERβ ligand treatment
Open accessAbstract
Treatment with either estradiol or an estrogen receptor (ER)α ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ERα vs. an ERβ ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ERα ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ERβ ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ERα ligand treatment was antiinflammatory in the systemic immune system, whereas ERβ ligand treatment was not. Also, ERα ligand treatment reduced CNS inflammation, whereas ERβ ligand treatment did not. Interestingly, treatment with either the ERα or the ERβ ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ERβ selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ERβ ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ERα.
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Estrogen receptor-α treatment inhibits TNF-α and IL-6.
“whereas estrogen receptor-α treatment inhibits TNF-α and IL-6 (Tiwari-Woodruff et al., 2007).”
From Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease (2017) · cites this paper as Tiwari-Woodruff et al., 2007
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Self-citation
- Authors
- Tiwari-Woodruff, S., Morales, L. B. J., Lee, R., & Voskuhl, R. R.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Voskuhl, Rhonda R.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-09-11
- Volume
- 104
- Issue
- 37
- Pages
- 14813-14818
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1976208
- OpenAlex
- W1976492591
- Cited by
- 234
- References
- 37
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 14 · 2018: 12 · 2017: 7 · 2016: 16 · 2015: 10 · 2014: 13 · 2013: 11 · 2012: 22
- FWCI
- 12.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Sclerosis Society
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS45443, R01NS045443)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- estrogen receptor alpha, estrogen receptor beta, estradiol, neuroprotection, experimental autoimmune encephalomyelitis, multiple sclerosis, demyelination, neuroinflammation, neurodegeneration
- MeSH terms
- Animals, Anti-Inflammatory Agents, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Estradiol, Female, Homozygote, Humans, Immunohistochemistry, Ligands, Mice, Inbred C57BL, Nitriles, Ovariectomy, Phenols, Propionates, Pyrazoles, Neuroprotective Agents, Selective Estrogen Receptor Modulators, Estrogen Receptor alpha, Estrogen Receptor beta, Mice
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