Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.
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 alpha (ERalpha) 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, ERalpha-, or ERbeta-deficient mice, and each was treated with the highly selective ERalpha agonist, propyl pyrazole triol, to determine the effect on clinical outcomes, as well as on inflammatory and neurodegenerative changes. ERalpha ligand treatment ameliorated clinical disease in both wild-type and ERbeta knock-out mice, but not in ERalpha knock-out mice, thereby demonstrating that the ERalpha ligand maintained ERalpha selectivity in vivo during disease. ERalpha ligand treatment also induced favorable changes in autoantigen-specific cytokine production in the peripheral immune system [decreased TNFalpha, interferon-gamma, and interleukin-6, with increased interleukin-5] and decreased CNS white matter inflammation and demyelination. Interestingly, decreased neuronal staining [NeuN+ (neuronal-specific nuclear protein)/beta3-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 ERalpha ligand significantly reduced this gray matter pathology. In conclusion, treatment with an ERalpha ligand is highly selective in vivo, mediating both anti-inflammatory and neuroprotective effects in EAE.
Morales
Laurie Beth J
LB
Multiple Sclerosis Program, Department of Neurology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Loo
Kyi Kyi
KK
Liu
Hong-Biao
HB
Peterson
Cory
C
Tiwari-Woodruff
Seema
S
Voskuhl
Rhonda R
RR
D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control* / Q000652:urine; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D005260:Female; D006023:Glycoproteins; D007150:Immunohistochemistry / Q000379:methods; D017493:Leukocyte Common Antigens / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010052:Ovariectomy / Q000379:methods; D010446:Peptide Fragments; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology
D000943:Antigens, Differentiation; D016207:Cytokines; D047628:Estrogen Receptor alpha; D006023:Glycoproteins; D052119:Lysosomal-Associated Membrane Protein 2; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D020845:Selective Estrogen Receptor Modulators; C036763:monocyte-macrophage differentiation antigen; C445081:myelin oligodendrocyte glycoprotein (35-55); D017493:Leukocyte Common Antigens; D010751:Phosphopyruvate Hydratase