SELECTIVE ESTROGEN RECEPTOR MODULATORS DECREASE INFLAMMATORY RESPONSE OF GLIAL CELLS

AREVALO MA; DIZ-CHAVES Y; SANTOS-GALINDO M; BELLINI MJ; GARCIA-SEGURA LM

TORINO, ITALIA

Congreso; 6th International Meeting STEROIDS AND NERVOUS SYSTEM; 2011

Neuroinflammation is a common feature of many neurological disorders, and it is often accompanied by activation of glial cells and the release of proinflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. The ovarian hormone estradiol exerts protective actions in the central nervous system that, at least in part, could be mediated by a reduction of local inflammation. Several selective estrogen receptor modulators (SERMs) may also exert neuroprotective effects by controlling local brain inflammation, which is mainly regulated by microglia and astroglia. Tamoxifen and raloxifene, two SERMs that are currently used in clinical practice for the treatment of breast cancer and osteoporosis, are able to decrease the inflammatory response caused by lipopolysaccharide (LPS), a bacterial endotoxin known to cause neuroinflammation, in mouse and rat microglia cells in vitro [1]. Tamoxifen and raloxifene are also able to reduce microglia activation in the central nervous system of male and female rats in vivo after the peripheral administration of LPS [2]. In addition, tamoxifen decreases microglial inflammatory response induced by irradiation [3]. Furthermore, treatment with tamoxifen and raloxifene resulted in a significant reduction in the number of reactive astrocytes in the hippocampus of young, middle-aged and older female rats after a stab wound injury [4]. Tamoxifen, raloxifene and the new SERMs ospemifene and bazedoxifene have been also shown to decrease the expression and release of IL-6 and IP-10 in cultured astrocytes exposed to LPS. Ospemifene and bazedoxifene exert antiinflammatory effects in astrocytes by a mechanism involving classical estrogen receptors and by the inhibition of LPS-induced NFkB p65 transactivation [5]. The results suggest that estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of pro-inflammatory molecules by glial cells.Reference List1. Suuronen T, Nuutinen T, Huuskonen J, Ojala J, Thornell A, Salminen A. Anti-inflammatory effect of selective estrogen receptor modulators (SERMs) in microglial cells. Inflamm Res 2005; 54: 194-203.2. Tapia-Gonzalez S, Carrero P, Pernia O, Garcia-Segura LM, Diz-Chaves Y. Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs. J Endocrinol 2008; 198: 219-230.3. Liu JL, Tian DS, Li ZW, Qu WS, Zhan Y, Xie MJ, Yu ZY, Wang W, Wu G. Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo. Brain Res 2010; 1316: 101-111.4. Barreto G, Santos-Galindo M, Diz-Chaves Y, Pernia O, Carrero P, Azcoitia I, Garcia-Segura LM. Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. Endocrinology 2009; 150: 5010-5015.5. Cerciat M, Unkila M, Garcia-Segura LM, Arevalo MA. Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro. Glia 2010; 58: 93-102.