Treatment with an Estrogen Receptor α Ligand Is Neuroprotective in Experimental Autoimmune Encephalomyelitis

摘要

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 α (ERα) 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, ERα-, or ERβ-deficient mice, and each was treated with the highly selective ERα agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ERα ligand treatment ameliorated clinical disease in both wild-type and ERβ knock-out mice, but not in ERα knock-out mice, thereby demonstrating that the ERα ligand maintained ERα selectivity in vivo during disease. ERα ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFα, interferon-γ, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/β3-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 ERα ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ERα ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.