Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Abstract

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ER and ER . The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17 -estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ER -selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ER -selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ER agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ER -selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

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).…”

Estriol has different effects from 17β-estradiol in modulating mouse splenocyte function under inflammatory conditions

“…Several earlier studies showed that estrogens (particularly E 3 ) could modulate antigen-specific immune response in autoimmune disease animal models, including those for experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) (Soldan et al, 2003;Palaszynski et al, 2004;Elloso et al, 2005). These autoimmune conditions are usually induced by injection of specific antigens that are emulsified with CFA.…”

“…It is known that both ER sub-types are expressed in cells of the mouse immune system (Smithson et al, 1995;Igarashi et al, 2001;Sakazaki et al, 2002), and that both E 3 and E 2 can activate ERα and ERβ signaling in these cells to modulate immune responses via their genomic actions (Salem et al, 2000;Maret et al, 2003;Polanczyk et al, 2003;Elloso et al, 2005;Baker et al, 2004). When E 3 and E 2 exert a similar modulating effect on certain immune system functions, it is likely that their actions are mediated through activation of the ERα and/or ERβ system(s), since both estrogens can bind to and activate these two receptor systems.…”

Studies on estrogen receptor (ER) α and β responses on gene regulation in peripheral blood leukocytes in vivo using selective ER agonists

“…The beneficial effects, particularly of ERa ligands on suppression of experimental autoimmune encephalomyelitis have been shown (Elloso et al 2005). E 2 has been shown to decrease neutrophil infiltration in the lung following trauma hemorrhage in mice (Hildebrand et al 2006), and a selective ERb ligand (ERB-041) was shown to have potent anti-inflammatory activity in a rat model of arthritis (Follettie et al 2006).…”