Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand

Abstract

Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ERβ ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERβ is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ERβ-null mice. Here we investigated the potential role of ERβ expression in cells of oligodendrocyte (OL) lineage in ERβ ligand-mediated neuroprotection. To this end, we selectively deleted ERβ in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ERβ CKO on ERβ ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ERβ CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ERβ CKO mice. However, DPN treatment significantly increased brainderived neurotrophic factor levels in ERβ CKO mice. These findings demonstrate that signaling through ERβ in OLs is essential for the beneficial myelination effects of the ERβ ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.is an inflammatory, demyelinating neurodegenerative disease characterized by physical, and often cognitive, deficits that can progress to severe debilitation. Although current MS treatments exist in the form of immunomodulatory or immunosuppressive agents, these treatments fail to halt disease progression and are not directly neuroprotective.Building on a wealth of research supporting a role for estrogens in neuroprotection, we have demonstrated that treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) attenuates clinical disease, neurodegeneration, and axon demyelination and improves axon conduction (1-4). Notably, these effects were observed with both prophylactic and therapeutic treatment regimens, and they occurred in the presence of peripheral cytokine production and central nervous system (CNS) inflammation. Evidence of direct neuroprotection by an ERβ ligand is welcomed, because it circumvents ERα-mediated adverse effects of synthetic estrogens [i.e., increased breast and uterine endometrial growth in females and feminizing effects in males (5)].Because ERs are present in various cell types in the peripheral immune system and CNS, including cells of oligodendrocyte (OL) lineage, it is difficult to assess which cell type(s) mediate ERβ ligand-conferred neuroprote...

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

“…Using conditional gene knockout mice, we have shown that the functional beneficial effects of the less-selective ERβ agonist DPN in EAE mice are largely attributable to its action on ERβ in OL lineage cells (6). Further, increased BDNF expression in DPN-administered mice lacking ERβ in OLs is not sufficient to reduce clinical disease or demyelination or to increase the PI3K/AKT/mTOR pathway activation, although it may explain partial improvement of axonal loss and conduction (5,6). It would follow that the functional benefits of therapeutic Ind-Cl, a more selective ERβ agonist, are at least partly attributable to the drug's actions on ERβ in OL lineage cells.…”

“…To assess Ind-Cl effects on the potentially BDNF-mediated PI3K/Akt/mTOR pathway [also modulated by DPN (6,(19)(20)(21)] in EAE mice, CC homogenates were probed for relevant proteins Fig. 3.…”

“…Our recent work has demonstrated promising neuroprotective effects of the estrogen receptor (ER) β agonist 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) (4,5). Although DPN, acting through ERβ, has a desirable palliative effect in EAE, it possesses only 70-fold binding selectivity for ERβ over ERα and lacks anti-inflammatory effects (6,7). A more selective ERβ agonist capable of immunomodulation would be more efficacious in treating inflammatory demyelinating neurodegeneration.…”

Estrogen-mediated protection of experimental autoimmune encephalomyelitis: Lessons from the dissection of estrogen receptor-signaling in vivo

“…[73] In this model, DPN-treatment had no effect on peripheral auto-antigen-specific T-cell responses and did not reduce spinal cord inflammation during EAE. Though ineffective Sophie Laffont, et al Estrogen-mediated protection of EAE on inflammation, DPN-treatment was shown to protect mice from demyelination and axonal loss, and to restore motor function.…”

“…Though ineffective Sophie Laffont, et al Estrogen-mediated protection of EAE on inflammation, DPN-treatment was shown to protect mice from demyelination and axonal loss, and to restore motor function. [29,73] Moreover, using conditional ERβ knock-out mouse models, it was reported that DPN-conferred neuroprotection was not dependent on ERβ-signaling in astrocytes nor in neurons, suggesting a role for oligodendrocytes as the primary targets of this ERβ ligand.[74] Indeed, DPN was shown to act through ERβ-signaling in oligodendrocytes not only to prevent demyelination, but also to promote remyelination.[75] Thus, it has been proposed that such ERβ-ligands could be used in combination with anti-inflammatory drugs in MS patients. [76] Beside ERβ-ligands, evidence also exists for ERα-mediated neuroprotective effects.…”