Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

Document Type : Original Article


1 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Department of Physiology, Kerman University of Medical Sciences, Kerman, Iran


Objective(s):Estrogen (E2) has neuroprotective effects on blood-brain-barrier (BBB) after traumatic brain injury (TBI). In order to investigate the roles of estrogen receptors (ERs) in these effects, ER-α antagonist (MPP) and, ER-β antagonist (PHTPP), or non-selective estrogen receptors antagonist (ICI 182780) were administered.
Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg) or oil were administered 30 min after TBI. 1 dose (150 µg/Kg) of each of MPP, PHTPP, and (4 mg/kg) ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content) and brain edema (brain water content) evaluated 5 hr and 24 hr after the TBI were evaluated, respectively.
Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P<0.01). The brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05).The inhibitory effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content.
Conclusion: A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors.


1. Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain pathology 2004; 14:215-222.
2. Cederberg D, Siesjö P. What has inflammation to do with traumatic brain injury? Childs Nerv Syst 2010; 26:221-226. 
3. Venero JL, Machado A, Cano J. Importance of aquaporins in the physiopathology of brain edema. Curr Pharm Des 2004; 10:2153-2161.
4. Brown CM, Mulcahey TA, Filipek NC, Wise PM. Production of proinflammatory cytokines and chemokines during neuroinflammation. novel roles for estrogen receptors α and β. Endocrinology 2010; 151:4916-4925.
5. Alkayed NJ, Goto S, Sugo N, Joh HD, Klaus J, Crain BJ, et al. Estrogen and Bcl-2 gene induction and effect of transgene in experimental stroke. J Neurosci 2001; 21:7543-7550.
6. Liu R, Wen Y, Perez E, Wang X, Day AL, Simpkins JW, et al. 17β-Estradiol attenuates blood–brain barrier disruption induced by cerebral ischemia–reperfusion injury in female rats. Brain Res 2005; 1060:55-61.
7. Shahrokhi N, Khaksari M, Soltani Z, Mahmoodi M, Nakhaee N. Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Can J Physiol Pharmacol 2010; 88:414-421.
8. Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007; 28:521-574.
9. Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 2009; 30:201-211.
10. Mazzucco C, Lieblich SE, Bingham BI, Williamson MA, Viau V, Galea LA. Both estrogen receptor α and estrogen receptor β agonists enhance cell proliferation in the dentate gyrus of adult female rats. Neuroscience 2006; 141:1793-1800.
11. Vegeto E, Benedusi V, Maggi A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front Neuroendocrinol 2008; 29:507-519.
12. Harris H, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, et al. Evaluation of an estrogen receptor-beta agonist in animal models of human disease. Endocrinology 2003; 144:4241-4249.
13. Khaksari M, Soltani Z, Shahrokhi N, Moshtaghi G, Asadikaram G. The role of estrogen and progesterone, administered alone and in combination, in modulating cytokine concentration following traumatic brain injury. Can J Physiol Pharmacol 2010; 89:31-40.
14. Keshavarzi Z, Khaksari Hadad M, Zahedi MJ, Bahrami A. The effects of female sex steroids on gastric secretory responses of rat following traumatic brain injury. Iran J Basic Med Scie 2011; 14:231-239.
15. Khaksari M, Mahmmodi R, Shahrokhi N, Shabani M, Joukar S, Aqapour M. The effects of shilajit on brain edema, intracranial pressure and neurologic outcomes following the traumatic brain injury in rat. Iran J Basic Med Sci 2013; 16:858-864.
16. O'Connor CA, Cernak I, Vink R. Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res 2005; 1062:171-174.
17. Santollo J, et al. Activation of ERα is necessary for estradiol's anorexigenic effect in female rats. Hormones and behavior 2010; 58:872-877.
18. Davis AM, Ellersieck MR, Grimm KM, Rosenfeld CS. The effects of the selective estrogen receptor modulators, methyl‐piperidino‐pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus. Mol Reprod Dev 2006; 73:1034-1044.
19. Cotroneo MS, Fritz WA, Lamartiniere CA. Dynamic profiling of estrogen receptor and epidermal growth factor signaling in the uteri of genistein-and estrogen-treated rats. Food Chem Toxicol  2005; 43:637-645.
20. Will B, Galani R, Kelche C, Rosenzweig MR. Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training. Prog Neurobiol 2004; 72:167-182.
21. Szymczak S, Kalita K, Jaworski J, Mioduszewska B, Savonenko A, Markowska Aet al. Increased estrogen receptor β expression correlates with decreased spine formation in the rat hippocampus. Hippocampus 2006; 16:453-463.
22. Evans MJ, Harris HA, Miller CP, Karathanasis SK, Adelman SJ. Estrogen receptors α and β have similar activities in multiple endothelial cell pathways. Endocrinology 2002; 143:3785-3795.
23. Morissette M, Le Saux M, D'Astous M, Jourdain S, Al Sweidi S, Morin Net al. Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol 2008; 108:327-338.
24. Sun J,  Huang YR, Harrington WR, Sheng S, Katzenellenbogen JA, Katzenellenbogen BS. Antagonists selective for estrogen receptor α. Endocrinology 2002; 143:941-947.
25. Dhillon S, Belsham D. Estrogen inhibits NPY secretion through membrane-associated estrogen receptor (ER)-α in clonal, immortalized hypothalamic neurons. Int J Obes (Lond)  2011; 35:198-207.
26. SantolloJ, Eckel LA. Effect of a putative ERα antagonist, MPP, on food intake in cycling and ovariectomized rats. Physiol Behav 2009; 97:193-198.
27. Bains M, Cousins JC, Roberts JL. Neuroprotection by estrogen against MPP-induced dopamine neuron death is mediated by ERα in primary cultures of mouse mesencephalon. Exp Neurol 2007; 204:767-776.
28. Miller NR, Jover T, Cohen HW, Zukin RS, Etgen AM. Estrogen can act via estrogen receptor α and β to protect hippocampal neurons against global ischemia-induced cell death. Endocrinology 2005; 146:3070-3079.
29. Wong JK, Le HH, Zsarnovszky A, Belcher SM. Estrogens and ICI182, 780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase. J Neurosci  2003; 23:4984-4995.
30. Santollo J, Katzenellenbogen BS, Katzenellenbogen JA, Eckel LA. Activation of ERα is necessary for estradiol's anorexigenic effect in female rats. Horm Behav 2010; 58:872-877.
31. Harrington WR,  Sheng S, Barnett DH, Petz LN, Katzenellenbogen JA, Katzenellenbogen BS. Activities of estrogen receptor alpha-and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression. Mol Cell Endocrinol 2003; 206:13-22.
32. Sárvári M, Hrabovszky E, Kalló I, Solymosi N, Tóth K, Likó I, et al. Estrogens regulate neuroinflammatory genes via estrogen receptors a and b in the                  frontal cortex of middle-aged female rats. J Neuroinflammation 2011; 8:82-89.
33. Zhang YQ,  Shi J, Rajakumar G, Day AL, Simpkins JW. Effects of gender and estradiol treatment on focal brain ischemia. Brain Res 1998; 784:321-324.
34. Baker AE, Brautigam VM, Watters JJ. Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor β. Endocrinology 2004; 145:5021-5032.
35. Waters EM, Mitterling K, Spencer JL, Mazid S, McEwen BS, Milner TA. Estrogen receptor alpha and beta specific agonists regulate expression of synaptic proteins in rat hippocampus. Brain Res  2009; 1290:1-11.
36. Davis L,  Katsu Y, Iguchi T, Lerner DT, Hirano T, Grau EG. Transcriptional activity and biological effects of mammalian estrogen receptor ligands on three hepatic estrogen receptors in Mozambique tilapia. J Steroid Biochem Mol Biol 2010; 122:272-278.
37. Somjen D,  Katzburg S, Sharon O, Grafi-Cohen M, Knoll E, Stern N. The effects of estrogen receptors α‐and β‐specific agonists and antagonists on cell proliferation and energy metabolism in human bone cell line. J Cell Biochem 2011; 112:625-632.
38. Aguirre C, Jayaraman A, Pike C, Baudry M. Proges-terone inhibits estrogen‐mediated neuroprotection against excitotoxicity by down‐regulating estrogen receptor‐β. J Neurochem 2010; 115:1277-1287.
39. Shimada K, Kitazato KT, Kinouchi T, Yagi K, Tada Y, Satomi J, et al. Activation of estrogen receptor-α and of angiotensin-converting enzyme 2 suppresses ischemic brain damage in oophorectomized rats. Hypertension  2011; 57:1161-1166.
40. Carswell HV, Bingham D, Wallace K, Nilsen M, Graham DI,  Dominiczak AF, et al. Differential effects of 17beta-estradiol upon stroke damage in stroke prone and normotensive rats. J Cereb Blood Flow Metab 2004; 24:298-304.
41. Bliedtner A, Zierau O, Albrecht S, Liebhaber S, Vollmer G. Effects of genistein and estrogen receptor subtype-specific agonists in ArKO mice following
different administration routes. Mol Cell Endocrinol  2010; 314:41-52.
42. Patisaul HB, Burke KT, Hinkle RE, Adewale HB, Shea D. Systemic administration of diarylpropionitrile (DPN) or phytoestrogens does not affect anxiety-related behaviors in gonadally intact male rats. Horm Behav 2009; 55:319-328.
43. Sierens JE, Scobie GA, Wilson J, Saunders PT. Cloning of oestrogen receptor beta from Old and New World primates: identification of splice variants and functional analysis. J Mol Endocrinol 2004; 32:703-718.
44. Mattsson A, Olsson JA, Brunström B. Activation of estrogen receptor alpha disrupts differentiation of the reproductive organs in chicken embryos. Gen Comp Endocrinol 2011; 172:251-259.
45. Kansra S, Chen S, Bangaru ML, Sneade L, Dunckley JA, Ben-Jonathan N. Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation. PLoS One  2010; 5: e10060.
46. Eckel LA. The ovarian hormone estradiol plays a crucial role in the control of food intake in females. Physiol Behav  2011; 104:517-524.[M1]