Estradiol effects on cortical reactive astrogliosis after brain injury involve cannabinoid receptors CB1 and CB2

LÓPEZ-RODRÍGUEZ, AB; MATEOS VICENTE, B; ROMERO-ZERBO SY; RODRIGUEZ-RODRIGUEZ N; BELLINI MJ; RODRIGUEZ DE FONSECA F; BERMUDEZ-SILVA FJ; AZCOITIA I; GARCIA-SEGURA LM; VIVEROS MP

TORINO, ITALIA

Congreso; 7TH MEETING STEROIDS AND NERVOUS SYSTEM,; 2013

Brain injuries activate inflammatory responses and trigger the release of potential harmful molecules such as cytokines or reactive oxygen species leading to a worsening in secondary damage [7]. One of the most studied aspects is the astrocitic reactivity and the glial scar formation after lesion. Previous studies of the group show that the neuroactive steroid estradiol reduces reactive astroglia after brain injury [1,2,4,5] by mechanisms similar to those involved in the regulation of reactive gliosis by endocannabinoids, for example inhibiting NFKB-induced transcription of proinflammatory chemokines and cytokines [3,6]. The similitude in the anti-inflammatory actions of cannabinoids and estrogens on astrocytes suggests a possible interaction of these two families of molecules in the regulation of reactive astroglia. To test this hypothesis, in this study, we have assessed the effect of estradiol, the cannabinoid CB1 antagonist/inverse agonist AM251, and the cannabinoid CB2 antagonist/inverse agonist AM630 on reactive astroglia in the cerebral cortex of male rats after a stab wound brain injury. Our results showed that estradiol reduced the number of vimentin immunoreactive astrocytes and the number of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes in the proximity of the wound. The protective effect of estradiol was significantly inhibited by the administration of either CB1 or CB2 receptor antagonists. The effect of estradiol may be in part mediated by alterations in endocannabinoid signaling because the hormone also altered the levels of mRNA for CB2 receptor in the injured cerebral cortex as well as the levels of monoacylglycerol lipase (MAGL) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), two enzymes involved in the synthesis and metabolism of endocannabinoids. These findings suggest that estradiol may decrease reactive astroglia in the injured brain by regulating the activity of the endocannabinoid system . Acknowledgements: Instituto de Salud Carlos III, Redes temáticas de Investigación Cooperativa en salud, RD06/0001/1013. GRUPO UCM 951579. Reference list [1] Barreto G, Veiga S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D. Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone. Eur J Neurosci. 25:3039-3046 (2007). [2] Barreto G, Santos-Galindo M, Diz-Chaves Y, Pernía 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 150, 5010-5015 (2009). [3] Cerciat M, Unkila M, Garcia-Segura LM, Arevalo MA. 2010. 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. 58:93-102 (2010)