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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 [NeuNϩ (neuronal-specific nuclear protein)/␤3-tubulinϩ/Nissl], accompanied by increased immunolabeling of microglial/monocyte (Mac 3ϩ) 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.

Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor α (ERα). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERα expression was shown at both the RNA and protein levels in these tissues. Use of ERα knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERα in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.

PS protects against development of EAE by reducing infiltration and inflammatory activity of immune cells into CNS of treated mice, thereby decreasing demyelination associated with EAE. These results provide evidence to support PS as a preventative agent that helps to protect against the development of inflammation-driven disease, such as MS.

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