17beta‐estradiol protects oligodendrocytes from cytotoxicity induced cell death

Abstract

During pregnancy, changes in circulating levels of hormones, including estrogens, correlates with a significant decrease in the relapse incidence in women with Multiple Sclerosis (MS). In the present study, we demonstrate that both primary and cell line cultures of rat oligodendrocytes express the estrogen receptor (ER)-a and ERb estrogen receptors in the cytosol and nucleus, and that nuclear compartmentalization becomes more pronounced as the cells mature. Moreover, 17b-estradiol significantly decreases the cytotoxic effects of the peroxynitrite generator 3-(4-morpholinyl)-sydnonimine (SIN-1) in both immature and mature oligodendrocytes in a dose dependent manner. This protective mechanism requires pretreatment with 17b-estradiol and is blocked by ICI 182,780, a selective ERa/ERb antagonist. These results strongly suggest that 17b-estradiol protects oligodendrocytes against SIN-1 mediated cytotoxicity through the activation of the estrogen receptors and provides new insights into the roles of the estrogen signaling pathways in myelin forming cells that are lost in demyelinating disorders.

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

“…The level of ERa (but not ERb) mRNA is higher in female than male OLs (Takao et al, 2004). However, in the present work, the staining pattern of OLs by immunohistochemistry (Fig.…”

“…Moreover, OL membranes also had a weakly stained band of 65 kDa. Takao et al (2004) reported that rat brain had 65 and 60 kDa forms of ERa. Smaller ERa isoforms have also been reported.…”

“…Moreover, they reported that endogenous levels of 17a-estra-diol are significantly elevated in postnatal and adult mouse brain in both sexes . ERa and ERb are expressed in the cytosol and membrane sheets in addition to the nuclei of oligodendrocytes (OLs) derived from rodent brain (Arvanitis et al, 2004;Takao et al, 2004;Zhang et al, 2004). A membrane form of ER is also expressed in isolated bovine brain myelin and in situ in rat myelin surrounding axons, colocalized with myelin basic protein (Arvanitis et al, 2004).…”

“…However, the function of these extranuclear receptors in OLs is not known. Prolonged exposure to estradiol stimulates proliferation and differentiation of OLs (Jung-Testas et al, 1992;Marin-Husstege et al, 2004;Zhang et al, 2004), and protects them from cell death because of hyperoxia or cytotoxic agents (Gerstner et al, 2007;Takao et al, 2004), but these effects may have been mediated through the nuclear receptor. To provide evidence for a role for a membrane ER in rapid signaling in OLs, we have investigated the effect of both 17a-and 17b-estradiol on short-term activation of several signaling pathways known to be involved in development of myelinating cells, involving MAPK, Akt, and GSK-3b (Cui et al, 2005;Khorchid et al, 1999;Ogata et al, 2004;Palacios et al, 2005).…”

Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

“…Similarly, the ability of estrogens to antagonize these glutamate-induced reductions in protein phosphatases suggests that this action is common to estrogen protection in both oxidative stress and excitotoxicity in neurons. In addition, experimental data from various studies have shown not only the ability of estrogen to protect glial cells from various toxins (Bishop and Simpkins, 1994;Haghighat et al, 2004;Takao et al, 2004) but also the mediation of glial cells in estrogen neuroprotection (Sortino et al, 2004;Wynne and Saldanha, 2004). Therefore, it is important to understand the mechanism of estrogen actions in both neurons and glia.…”