title: Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis.
abstract: Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE.
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA. amg@ucla.edu
authors.forename: Allan J
authors.initials: AJ
authors.lastname: MacKenzie-Graham
authors.forename: Gilda A
authors.initials: GA
authors.lastname: Rinek
authors.forename: Andrea
authors.initials: A
authors.lastname: Avedisian
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Morales
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Umeda
authors.forename: Benoit
authors.initials: B
authors.lastname: Boulat
authors.forename: Russell E
authors.initials: RE
authors.lastname: Jacobs
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
mesh_terms: D000818:Animals; D001284:Atrophy; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000819:agonists; D047629:Estrogen Receptor beta / Q000819:agonists; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018696:Neuroprotective Agents