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The Journal of Neuroscience, June 21, 2006, 26(25):6823-6833; doi:10.1523/JNEUROSCI.0453-06.2006

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Neurobiology of Disease
Treatment with an Estrogen Receptor Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

Laurie Beth J. Morales, Kyi Kyi Loo, Hong-biao Liu, Cory Peterson, Seema Tiwari-Woodruff, and Rhonda R. Voskuhl

Multiple Sclerosis Program, Department of Neurology, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Rhonda R. Voskuhl, Multiple Sclerosis Program, Department of Neurology, University of California, Los Angeles, Neuroscience Research Building 1, Room 475D, 635 Charles Young Drive South, Los Angeles, CA 90095. Email: rvoskuhl{at}ucla.edu

Multiple sclerosis is an inflammatory, neurodegenerative disease for which experimental autoimmune encephalomyelitis (EAE) is a model. Treatments with estrogens have been shown to decrease the severity of EAE through anti-inflammatory mechanisms. Here we investigated whether treatment with an estrogen receptor (ER) ligand could recapitulate the estrogen-mediated protection in clinical EAE. We then went on to examine both anti-inflammatory and neuroprotective mechanisms. EAE was induced in wild-type, ER-, or ER-deficient mice, and each was treated with the highly selective ER agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ER ligand treatment ameliorated clinical disease in both wild-type and ER knock-out mice, but not in ER knock-out mice, thereby demonstrating that the ER ligand maintained ER selectivity in vivo during disease. ER ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNF, interferon-, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/3-tubulin+/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3+) cells surrounding these abnormal neurons, was observed in gray matter of spinal cords of EAE mice at the earliest stage of clinical disease, 1–2 d after the onset of clinical signs. Treatment with either estradiol or the ER ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ER ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.

Key words: multiple sclerosis; experimental autoimmune encephalomyelitis; estrogen; cytokines; neuron; microglia

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Received Jan. 31, 2006; revised May 15, 2006; accepted May 18, 2006.

Correspondence should be addressed to Rhonda R. Voskuhl, Multiple Sclerosis Program, Department of Neurology, University of California, Los Angeles, Neuroscience Research Building 1, Room 475D, 635 Charles Young Drive South, Los Angeles, CA 90095. Email: rvoskuhl{at}ucla.edu

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