2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

• Published in: American journal of physiology: endocrinology and metabolism 2016-03, Vol.310 (5), p.E313-E322
• Main Authors: Schaufelberger, Sara A, Rosselli, Marinella, Barchiesi, Federica, Gillespie, Delbert G, Jackson, Edwin K, Dubey, Raghvendra K
• Format: Article
• Language: English
• Subjects: Animals; Call for Papers; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors - pharmacology; Cell Proliferation - drug effects; Cytochrome P-450 Enzyme Inhibitors - pharmacology; DNA - biosynthesis; DNA - drug effects; Estradiol - analogs & derivatives; Estradiol - pharmacology; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - antagonists & inhibitors; Estrogen Receptor beta - drug effects; Estrogen Receptor beta - metabolism; Estrogens - pharmacology; Mice; Microglia - drug effects; Microglia - metabolism; Phagocytosis - drug effects; Tubulin Modulators - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00418.2015

17β-Estradiol (estradiol) inhibits microglia proliferation. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with little affinity for estrogen receptors (ERs). We hypothesize that 2-ME inhibits microglial proliferation and activation and contributes to estradiol's inhibitory effects on microglia. We compared the effects of estradiol, 2-hydroxyestradiol [2-OE; estradiol metabolite produced by cytochrome P450 (CYP450)], and 2-ME [formed by catechol-O-methyltransferase (COMT) acting upon 2-OE] on microglial (BV2 cells) DNA synthesis, cell proliferation, activation, and phagocytosis. 2-ME and 2-OE were approximately three- and 10-fold, respectively, more potent than estradiol in inhibiting microglia DNA synthesis. The antimitogenic effects of estradiol were reduced by pharmacological inhibitors of CYP450 and COMT. Inhibition of COMT blocked the conversion of 2-OE to 2-ME and the antimitogenic effects of 2-OE but not 2-ME. Microglia expressed ERβ and GPR30 but not ERα. 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERβ agonist), but not 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (ERα agonist) or G1 (GPR30 agonist), inhibited microglial proliferation. The antiproliferative effects of estradiol, but not 2-OE or 2-ME, were partially reversed by ICI-182,780 (ERα/β antagonist) but not by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole (ERα antagonist) or G15 (GPR30 antagonist). Lipopolysaccharide increased microglia iNOS and COX-2 expression and phagocytosing activity of microglia; these effects were inhibited by 2-ME. We conclude that in microglia, 2-ME inhibits proliferation, proinflammatory responses, and phagocytosis. 2-ME partially mediates the effects of estradiol via ER-independent mechanisms involving sequential metabolism of estradiol to 2-OE and 2-ME. 2-ME could be of potential therapeutic use in postischemic stroke injuries. Interindividual differences in estradiol metabolism might affect the individual's ability to recover from stroke.