Investigation of 17 alfa-estradiol´s role in increasing inflammation in the central nervous system

• Grant number: 15/05801-7
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 01, 2015
• End date: July 31, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Everardo Magalhães Carneiro
• Grantee: Roberta de Souza Santos
• Supervisor: Deborah J. Clegg
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Cedars-Sinai Medical Center, United States

Abstract

The lack of ovarian-produced estrogens due to menopause causes inflammation, which is involved in the development of several diseases such as insulin resistance and type II diabetes. Males present more inflammatory diseases then adult females, maybe due to the protective effects of estrogens. Estrogens act in target tissues through estrogen receptors (ERs), such as classical ERalfa and ERbeta, which modulates nuclear and rapid membrane responses. Other types of ERs have been described recently, such as membrane ER-X. One conjugate of estrogen, 17 beta-estradiol, acts via nuclear ERalfa-regulated by PGC-1alfa, and inhibits the transcription of proinflammatory cytokines, such as TNF-alfa and IL-6. 17-beta is also involved in the synthesis of nitric oxide (NO) via membrane ERalfa. 17-alfa, another conjugate of estrogen, is produced locally in the central nervous system (CNS) and high levels were detected following surgically-induced menopause while other estrogens were decreased. Interestingly, adult males produce more 17-alfa then adult females. 17-alfa can bind to classical receptors, but its likely target in the CNS is membrane ER-X. When ER-X is activated by 17-alfa, it modulates the MAPK/ERK pathway, which is involved in the transcription of proinflammatory genes. Since the levels of 17-alfa and inflammatory processes are elevated following menopause, we hypothesize that 17 alfa-estradiol through ER-X is involved in the transcription of proinflammatory cytokines involving the MAPK/ERK pathway. Also, we speculate that 17-alfa via ER-X modulates PI3-K/Akt pathway to regulate NO synthesis. Finally, we think that the sexual dimorphism regarding central inflammation is due to the 17 alfa-estradiol. To test these hypotheses, we intend to directly study the effects of 17 alfa-estradiol in vitro and its impact in activating inflammatory processes in neurons and astrocytes. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SANTOS, ROBERTA S.; BATISTA, THIAGO M.; CAMARGO, RAFAEL L.; MORATO, PRISCILA N.; BORCK, PATRICIA C.; LEITE, NAYARA C.; KURAUTI, MIRIAN A.; WANSCHEL, AMARYLIS C. B. A.; NADAL, ANGEL; CLEGG, DEBORAH J.; et al. Lacking of estradiol reduces insulin exocytosis from pancreatic beta-cells and increases hepatic insulin degradation. Steroids, v. 114, n. SI, p. 16-24, OCT 2016. (15/05801-7, 13/07607-8)

SANTOS, ROBERTA S.; DE FATIMA, LUCIANA A.; FRANK, AARON P.; CARNEIRO, EVERARDO M.; CLEGG, DEBORAH J.. The effects of 17 alpha-estradiol to inhibit inflammation in vitro. BIOLOGY OF SEX DIFFERENCES, v. 8, SEP 6 2017. (15/05801-7)

STOUT, MICHAEL B.; STEYN, FREDERIK J.; JURCZAK, MICHAEL J.; CAMPOREZ, JOAO-PAULO G.; ZHU, YI; HAWSE, JOHN R.; JURK, DIANA; PALMER, ALLYSON K.; XU, MING; PIRTSKHALAVA, TAMAR; et al. 17 alpha-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization. JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, v. 72, n. 1, p. 3-15, JAN 2017. (15/05801-7)

SANTOS, ROBERTA S.; BATISTA, THIAGO M.; CAMARGO, RAFAEL L.; MORATO, PRISCILA N.; BORCK, PATRICIA C.; LEITE, NAYARA C.; KURAUTI, MIRIAN A.; WANSCHEL, AMARYLIS C. B. A.; NADAL, ANGEL; CLEGG, DEBORAH J.; et al. Lacking of estradiol reduces insulin exocytosis from pancreatic beta-cells and increases hepatic insulin degradation. Steroids, v. 114, p. 9-pg., 2016-10-01. (13/07607-8, 15/05801-7)