Stroke Recovery Affected By Differences in Estradiol Metabolism
2-methoxyestradiol could be of therapeutic use in post-ischemic stroke injuries.
HealthDay News — 2-methoxyestradiol (2-ME), an endogenous metabolite of estradiol, inhibits proliferation, pro-inflammatory responses, and phagocytosis in microglia, according to a study published in the American Journal of Physiology-Endocrinology and Metabolism.
Sara A. Schaufelberger, from the University Hospital Zurich, and colleagues 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 on 2-OE) on microglial DNA synthesis, cell proliferation, activation, and phagocytosis.
The researchers found that for inhibition of microglia DNA synthesis, 2-ME and 2-OE were about 3- and 10-fold more potent that estradiol, respectively. Pharmacological inhibitors of CYP450 and COMT reduced the anti-mitogenic effects of estradiol. COMT inhibition blocked 2-OE to 2-ME conversion and the anti-mitogenic effects of 2-OE but not 2-ME. Microglia expressed estrogen receptor (ER)-β and GPR30, but did not express ER-α. Microglial proliferation was inhibited by an ER-β agonist, but not by an ER-α agonist or G1 (GPR30 agonist). An ERα/β antagonist (ICI182780) partially reversed the anti-proliferative effects of estradiol, but not 2-OE or 2-ME, while an ER-α antagonist or G15 (GPR30 antagonist) did not. 2-ME inhibited the effect of lipopolysaccharide, which increased microglia inducible nitric oxide synthase and cyclooxygenase-2 expression and the phagocytosing activity of microglia.
"2-ME could be of potential therapeutic use in post-ischemic stroke injuries," the authors write. "Inter-individual differences in estradiol metabolism might affect the individual's ability to recover from stroke."
Schaufelberger SA, Rosselli M, Barchiesi F, et al. 2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Inhibits Microglial Proliferation and Activation via an Estrogen Receptor-Independent Mechanism. Am J Physiol-Endoc M. 2016; doi: 10.1152/ajpendo.00418.2015.