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

Abstract

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.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Morales et al [170] demonstrated that treatment with an ERa ligand is sufficient to recapitulate the estrogen-mediated protection in EAE, consistent with a report by Elloso et al [69] that demonstrated that treatment with an ERa, but not an ERb, ligand could reduce acute EAE disease severity. The degree of preservation of neuronal integrity in the gray matter of estradiol and ERa ligand-treated mice with EAE in this study was striking, and this has major implications for neurodegenerative changes that occur ''beyond the lesion" in EAE and possibly MS.…”

“…The ERa selective ligand propyl pyrazole triol (PPT) provides neuroprotection and anti-inflammatory activities in brain in experimental models of neurodegenerative diseases, including ischemia [165], MPTP-induced neurotoxicity [52] and EAE ( [69,170]). The in vitro activity of PPT has been studied in neuronal cells [266], while our preliminary data demonstrate a direct anti-inflammatory activity of this ligand in microglia (unpublished results).…”

The localization and non‐genomic function of the membrane‐associated estrogen receptor in oligodendrocytes

“…Furthermore, the presence of mER in myelin (Arvanitis et al, 2004), which is a membranous product of the OL and lacks nuclei, indicates that estrogen may also play a role in myelin function. Animals pretreated with estradiol or PPT before immunization to induce EAE were protected from clinical signs of the disease via an ERa effect (Morales et al, 2006). Treatment with ERb ligands induced clinical protection later in disease (Tiwari-Woodruff et al, 2007).…”

“…After puberty, MS occurs two times more frequently in the female than the male (Czlonkowska et al, 2005;Hughes, 2004), but pregnancy has a protective effect (Confavreux et al, 1998). Treatment of MS in humans and experimental allergic encephalomyelitis (EAE) in mice by estrogens ameliorates these diseases (Bebo et al, 2001;Morales et al, 2006;Soldan et al, 2003). An immunomodulatory effect had been suspected (Lang, 2004), but it has recently been shown that in EAE, estradiol exerts its ameliorating effect via ERa receptors in CNS-resident cells, not in lymphocytes (Garidou et al, 2004).…”

Clinicopathological significance and prognostic value of leukemia‐related protein 16 expression in invasive ductal breast carcinoma

“…Activation of the ER signaling pathway plays an important role in multi-tissue development. (49)(50)(51)(52) Therefore, we propose that LRP16, a coactivator of ERa, may display an important function in the carcinogenesis and progression of breast cancer. Besides, with ER, PR and Ki-67 (all P < 0.05) we also found that LRP16 expression was correlated with FHIT expression (P = 0.015) and CD133 expression (P = 0.038), implying co-operation of those important gene markers in the mechanism of breast cancer.…”