Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment

Abstract

Treatment with either estradiol or an estrogen receptor (ER)␣ ligand has been shown to be both antiinflammatory and neuroprotective in a variety of neurological disease models, but whether neuroprotective effects could be observed in the absence of an antiinflammatory effect has remained unknown. Here, we have contrasted effects of treatment with an ER␣ vs. an ER␤ ligand in experimental autoimmune encephalomyelitis, the multiple sclerosis model with a known pathogenic role for both inflammation and neurodegeneration. Clinically, ER␣ ligand treatment abrogated disease at the onset and throughout the disease course. In contrast, ER␤ ligand treatment had no effect at disease onset but promoted recovery during the chronic phase of the disease. ER␣ ligand treatment was antiinflammatory in the systemic immune system, whereas ER␤ ligand treatment was not. Also, ER␣ ligand treatment reduced CNS inflammation, whereas ER␤ ligand treatment did not. Interestingly, treatment with either the ER␣ or the ER␤ ligand was neuroprotective, as evidenced by reduced demyelination and preservation of axon numbers in white matter, as well as decreased neuronal abnormalities in gray matter. Thus, by using the ER␤ selective ligand, we have dissociated the antiinflammatory effect from the neuroprotective effect of estrogen treatment and have shown that neuroprotective effects of estrogen treatment do not necessarily depend on antiinflammatory properties. Together, these findings suggest that ER␤ ligand treatment should be explored as a potential neuroprotective strategy in multiple sclerosis and other neurodegenerative diseases, particularly because estrogen-related toxicities such as breast and uterine cancer are mediated through ER␣.experimental autoimmune encephalomyelitis ͉ neuroprotection ͉ multiple sclerosis selective estrogen receptor modulators

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

“…In the search for effective MS treatments, much has been invested in estrogens and ER agonists because of their neuroprotective benefits (5,10,25,26). Different ERβ ligand analogs have distinct effects on gene transcription in signaling pathways for chromosome replication, cell death, and OPC differentiation (27).…”

“…'s laboratories (8)] was dissolved in 10% ethanol + 90% (vol/vol) Miglyol 812N (vehicle; Sasol) and administered s.c. daily at 5 mg/kg body weight. Control groups received (s.c.) either 0.04 mg/kg/d 17β-estradiol (E2) or 8 mg/kg/48 h DPN (4,10). Treatment was initiated at EAE postinduction day 0 (preEAE) or day 21 (post/peakEAE) and continued until day 40.…”

“…Formalin-fixed CNS sections were examined by immunohistochemistry (10). In parallel, CC was examined using EM (4).…”

“…Our previous work reveals reduced axon numbers and myelination in the DC and CC by EAE day 21 (10,13). Ind-Cl effects on axonal pathology and demyelination were evaluated.…”

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

“…A l'opposé, Tiwari-Woodruff et coll. ont montré que les deux REs étaient neuroprotecteurs quand seul le REα réduirait l'inflammation dans le système nerveux central (Tiwari-Woodruff et al, 2007).…”