Immunofluorescence images of spinal cord tissues stained with CD11c-GFP (green), ERĪ² (red) and nuclear stain DAPI (blue) with merged images for co-localization (yellow) on right. Top row: CD11c-cre-GFP+ control mice showed co-localization (white arrows) of CD11c-GFP and ERĪ². Bottom row: CD11c-cre-GFP+;ERĪ²fl/fl CKO mice did not show co-localization (white arrows). Orange arrows represent other cells in the CNS expressing ER&beta. NeuroscienceNews.com image is credited to Kim et al./Brain.
UCLA researchers reveal the mechanism behind how estrogen can protect CNS system damage in people with MS. The researchers report estrogen treatments have positive effects on immune cells in the brain and oligodendrocytes. Complementary actions on these two types provide protection from disease.
Multiple sclerosis is a chronic autoimmune, neurodegenerative disease marked by visual impairment, weakness and sensory loss, as well as cognitive decline. These symptoms emerge when inflammatory immune cells destroy the myelin sheath that surrounds axons. The third trimester of pregnancy has been previously shown to reduce relapse rates by approximately 70% as compared to before pregnancy, and other studies have shown benefit over the long term due to multiple pregnancies. An estrogen unique to pregnancy that is made by the fetus and placenta has been proposed by Dr. Rhonda Voskuhl and colleagues to mediate this pregnancy protection in both the MS mouse model as well as in two successfully completed clinical trials of estriol treatment in MS patients.
How that happens has remained a critical question. Voskuhl, who led the latest study, reported mouse studies showing that estrogen protected the brain from damage by activating a protein called estrogen receptor beta (ERb). Her new research identifies which cells within the brain are mediating this protective effect.
METHOD
The researchers first genetically eliminated ERb in either immune cells of the brain or in oligodendrocytes, the cells that make the myelin sheath, as a way of making cells unresponsive to estrogen during the MS like disease in mice. They then treated mice without or with ERb in these cells to ask if disease protection was lost or not. Loss of protection during treatment meant that the treatment was acting on the cell that had the receptor removed. Results showed that the estrogen-like treatment was acting on both immune cells of the brain as well as on oligodendrocytes, together resulting in repair of myelin and less disability.
IMPACT
Drug developers often optimize therapies by targeting only one single cell type. By contrast, this study confirms that this estrogen-like compound can combat MS via complementary effects on two distinct cell types. Voskuhl and other UCLA researchers are in fact now developing a next-generation estrogen-like compound with robust biochemical effects on oligodendrocytes and immune cells in the brain.
http://neurosciencenews.com/estrogen-multiple-sclerosis-8243/ https://academic.oup.com/brain/article/141/1/132/4710057
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