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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.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) result in inflammatory white matter lesions in the CNS. However, information is sparse with regard to the effects of autoimmune demyelinating disease on gray matter regions. Therefore, we studied the late effects of chronic EAE in C57BL/6 mice on the spinal cord gray matter using immunohistochemistry. Here, EAE induced marked astrocytic, microglial, and macrophage activation in the ventral horn gray matter, without any motoneuron loss. Activated caspase-3 was also increased in the ventral horn gray matter. Furthermore, activated poly (ADP-ribose) polymerase (PARP), another apoptotic marker, co-localized with myelin basic protein (MBP) of oligodendrocyte processes, but not with the oligodendroglial cell body marker, adenomatous polyposis coli gene clone CC1 (APC-CC1), or with neurofilament marker (RT-97) or synaptophysin of axonal arbors. However, there was no associated increase in the number of terminal deoxynucleotidyl transferase (TdT) mediated-dUTP nick end labeling positive nuclei in the spinal cord gray matter of EAE mice. In addition, co-localization of MBP and the low-affinity neurotrophin receptor, p75, was demonstrated, further supporting the notion of apoptotic oligodendrocyte process degeneration in the gray matter of EAE mice. Keywords multiple sclerosis; inflammation; mouse; degeneration; demyelination Multiple sclerosis (MS) is an immune-mediated disorder, which affects the CNS with inflammatory lesions and demyelination (Lucchinetti et al., 1998). In addition to the focal destruction of myelin in the white matter tracts of the brain and spinal cord, MS lesions may also exhibit transected axons (Trapp et al., 1998). The latter findings are of particular clinical importance, as neurological disability has been correlated with axonal loss in the spinal cord of chronic MS patients (Bjartmar et al., 2000). Interestingly, in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, a similar axonal loss in spinal cord white matter is correlated with permanent neurological disability (Wujek et al., 2002). Therefore, from a pathological perspective, the axonal transections encountered in MS and EAE may result in partial or complete neurological disconnection syndromes, which are similar to those encountered following traumatic brain and spinal cord injuries.In recent years, an emerging literature from the neuroimaging field has demonstrated pathologic changes remote from the inflammatory white matter lesions of MS and EAE. For . E-mail address: E-mail: LHavton@mednet.ucla.edu (L. A. Havton). Chard et al., 2002;Dalton et al., 2004). Gray matter atrophy has been similarly documented in the cerebellar cortical gray matter of mice with EAE (MacKenzie-Graham et al., 2006). However, pathological effects within gray matter structures remain unclear. NIH Public AccessThe goal of this study was to investigate long-term effects of EAE on spinal cord gray matter beyond the sites of inflammatory white matter lesions. Durin...

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