The Effects of Estrogen in Ischemic Stroke

Translational Stroke Research

Volumn 4, Issue 4, 2013, Pages 390-401

  Koellhoffer, Edward C ^a   McCullough, Louise D ^a  

^a UNIVERSITY OF CONNECTICUT HEALTH CENTER   (United States)

Author keywords

Aging; Estrogen; Sex; Stroke

Indexed keywords

ESTROGEN; GAMMA INTERFERON; INTERLEUKIN 10; INTERLEUKIN 18; INTERLEUKIN 1BETA; INTERLEUKIN 4; WARFARIN;

AGING; ANTICOAGULANT THERAPY; BRAIN ISCHEMIA; CELL DEATH; CEREBROVASCULAR ACCIDENT; CYTOKINE PRODUCTION; DRUG EFFECT; HUMAN; INFLAMMATION; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SEX DIFFERENCE;

AGED; AGED, 80 AND OVER; AGING; ANIMALS; BRAIN ISCHEMIA; CASPASES; CELL DEATH; CYTOKINES; DISEASE MODELS, ANIMAL; ENCEPHALITIS; EPIGENESIS, GENETIC; ESTROGENS; FEMALE; GENE EXPRESSION; HUMANS; MALE; MICE; POSTMENOPAUSE; RATS; RISK FACTORS; RODENTIA; SEX CHARACTERISTICS; SEX CHROMOSOMES; STROKE;

EID: 84879925352     PISSN: 18684483     EISSN: 1868601X     Source Type: Journal    
DOI: 10.1007/s12975-012-0230-5     Document Type: Review

References (149)

1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics-2012 update: a report from the American Heart Association. Circulation. 2012;125(1): e2-220. doi: 10. 1161/CIR. 0b013e31823ac046.
2. Sudlow CL, Warlow CP. Comparable studies of the incidence of stroke and its pathological types: results from an international collaboration. International Stroke Incidence Collaboration. Stroke. 1997;28(3): 491-9.
3. Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K. Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab. 2004;24(4): 458-66. doi: 10. 1097/00004647-200404000-00011.
4. Yu SW, Wang H, Dawson TM, Dawson VL. Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. Neurobiol Dis. 2003;14(3): 303-17.
5. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24): 1581-7. doi: 10. 1056/NEJM199512143332401.
6. Adams Jr HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5): 1655-711. doi: 10. 1161/STROKEAHA. 107. 181486.
7. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8): 2761-8. doi: 10. 1161/STROKEAHA. 108. 544957.
8. California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64(4): 654-9. doi: 10. 1212/01. WNL. 0000151850. 39648. 51.
9. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297(5579): 259-63. doi: 10. 1126/science. 1072221297/5579/259.
10. Eliasson MJ, Huang Z, Ferrante RJ, Sasamata M, Molliver ME, Snyder SH, et al. Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. J Neurosci. 1999;19(14): 5910-8.
11. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997;3(10): 1089-95.
12. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265(5180): 1883-5.
13. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci U S A. 1991;88(14): 6368-71.
14. Du L, Bayir H, Lai Y, Zhang X, Kochanek PM, Watkins SC, et al. Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. J Biol Chem. 2004;279(37): 38563-70. doi: 10. 1074/jbc. M405461200M405461200.
15. Turtzo LC, McCullough LD. Sex-specific responses to stroke. Future Neurol. 2010;5(1): 47-59. doi: 10. 2217/fnl. 09. 66.
16. Li H, Pin S, Zeng Z, Wang MM, Andreasson KA, McCullough LD. Sex differences in cell death. Ann Neurol. 2005;58(2): 317-21. doi: 10. 1002/ana. 20538.
17. Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008;7(10): 915-26. doi: 10. 1016/S1474-4422(08)70193-5.
18. Liu F, Li Z, Li J, Siegel C, Yuan R, McCullough LD. Sex differences in caspase activation after stroke. Stroke. 2009;40(5): 1842-8. doi: 10. 1161/STROKEAHA. 108. 538686.
19. Lang JT, McCullough LD. Pathways to ischemic neuronal cell death: are sex differences relevant? J Transl Med. 2008;6: 33. doi: 10. 1186/1479-5876-6-33.
20. Renolleau S, Fau S, Charriaut-Marlangue C. Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist. 2008;14(1): 46-52. doi: 10. 1177/1073858407308889.
21. Zhang L, Nair A, Krady K, Corpe C, Bonneau RH, Simpson IA, et al. Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice. J Clin Invest. 2004;113(1): 85-95. doi: 10. 1172/JCI18336.
22. Harry GJ, Kraft AD. Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology. 2012;33(2): 191-206. doi: 10. 1016/j. neuro. 2012. 01. 012.
23. Sheffield LG, Berman NE. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging. 1998;19(1): 47-55.
24. Liu F, Yuan R, Benashski SE, McCullough LD. Changes in experimental stroke outcome across the life span. J Cereb Blood Flow Metab. 2009;29(4): 792-802. doi: 10. 1038/jcbfm. 2009. 5.
25. Liu F, McCullough LD. Interactions between age, sex, and hormones in experimental ischemic stroke. Neurochem Int. 2012. doi: 10. 1016/j. neuint. 2012. 10. 003.
26. Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: a systematic review. Stroke. 2009;40(4): 1082-90. doi: 10. 1161/STROKEAHA. 108. 540781.
27. Armstrong-Wells J, Johnston SC, Wu YW, Sidney S, Fullerton HJ. Prevalence and predictors of perinatal hemorrhagic stroke: results from the kaiser pediatric stroke study. Pediatrics. 2009;123(3): 823-8. doi: 10. 1542/peds. 2008-0874.
28. Raju TN, Nelson KB, Ferriero D, Lynch JK. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3): 609-16. doi: 10. 1542/peds. 2007-0336.
29. Golomb MR, Dick PT, MacGregor DL, Curtis R, Sofronas M, de Veber GA. Neonatal arterial ischemic stroke and cerebral sinovenous thrombosis are more commonly diagnosed in boys. J Child Neurol. 2004;19(7): 493-7.
30. Golomb MR, Fullerton HJ, Nowak-Gottl U, Deveber G. Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study. Stroke. 2009;40(1): 52-7. doi: 10. 1161/STROKEAHA. 108. 521203.
31. Salih MA, Abdel-Gader AG, Al-Jarallah AA, Kentab AY, Alorainy IA, Hassan HH, et al. Stroke in Saudi children. Epidemiology, clinical features and risk factors. Saudi Med J. 2006;27 Suppl 1: S12-20.
32. Bonduel M, Sciuccati G, Hepner M, Pieroni G, Torres AF, Frontroth JP, et al. Arterial ischemic stroke and cerebral venous thrombosis in children: a 12-year Argentinean registry. Acta Haematol. 2006;115(3-4): 180-5. doi: 10. 1159/000090932.
33. Ingemarsson I. Gender aspects of preterm birth. BJOG. 2003;110 Suppl 20: 34-8.
34. Hintz SR, Kendrick DE, Vohr BR, Kenneth Poole W, Higgins RD. Gender differences in neurodevelopmental outcomes among extremely preterm, extremely-low-birthweight infants. Acta Paediatr. 2006;95(10): 1239-48. doi: 10. 1080/08035250600599727.
35. Sheiner E, Levy A, Katz M, Hershkovitz R, Leron E, Mazor M. Gender does matter in perinatal medicine. Fetal Diagn Ther. 2004;19(4): 366-9. doi: 10. 1159/00007796777967.
36. Di Renzo GC, Rosati A, Sarti RD, Cruciani L, Cutuli AM. Does fetal sex affect pregnancy outcome? Gend Med. 2007;4(1): 19-30.
37. Johnston MV, Hagberg H. Sex and the pathogenesis of cerebral palsy. Dev Med Child Neurol. 2007;49(1): 74-8. doi: 10. 1111/j. 1469-8749. 2007. 0199a. x.
38. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke. 2009;40(4): 1032-7. doi: 10. 1161/STROKEAHA. 108. 542894.
39. Niewada M, Kobayashi A, Sandercock PA, Kaminski B, Czlonkowska A. Influence of gender on baseline features and clinical outcomes among 17, 370 patients with confirmed ischaemic stroke in the international stroke trial. Neuroepidemiology. 2005;24(3): 123-8. doi: 10. 1159/000082999.
40. Roquer J, Campello AR, Gomis M. Sex differences in first-ever acute stroke. Stroke. 2003;34(7): 1581-5. doi: 10. 1161/01. STR. 0000078562. 82918.
41. Fukuda M, Kanda T, Kamide N, Akutsu T, Sakai F. Gender differences in long-term functional outcome after first-ever ischemic stroke. Intern Med. 2009;48(12): 967-73.
42. Arnold M, Halpern M, Meier N, Fischer U, Haefeli T, Kappeler L, et al. Age-dependent differences in demographics, risk factors, co-morbidity, etiology, management, and clinical outcome of acute ischemic stroke. J Neurol. 2008;255(10): 1503-7. doi: 10. 1007/s00415-008-0949-9.
43. Bhatnagar P, Sinha D, Parker RA, Guyler P, O'Brien A. Intravenous thrombolysis in acute ischaemic stroke: a systematic review and meta-analysis to aid decision making in patients over 80 years of age. J Neurol Neurosurg Psychiatry. 2011;82(7): 712-7. doi: 10. 1136/jnnp. 2010. 223149.
44. Engelter ST, Reichhart M, Sekoranja L, Georgiadis D, Baumann A, Weder B, et al. Thrombolysis in stroke patients aged 80 years and older: Swiss survey of IV thrombolysis. Neurology. 2005;65(11): 1795-8. doi: 10. 1212/01. wnl. 0000183702. 04080. 27.
45. Zeevi N, Kuchel GA, Lee NS, Staff I, McCullough LD. Interventional stroke therapies in the elderly: are we helping? AJNR Am J Neuroradiol. 2012;33(4): 638-42. doi: 10. 3174/ajnr. A2845.
46. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995;155(5): 469-73.
47. Lane DA, Lip GY. Female gender is a risk factor for stroke and thromboembolism in atrial fibrillation patients. Thromb Haemost. 2009;101(5): 802-5.
48. Alkayed NJ, Harukuni I, Kimes AS, London ED, Traystman RJ, Hurn PD. Gender-linked brain injury in experimental stroke. Stroke. 1998;29(1): 159-65. discussion 66.
49. Hart RG, Eikelboom JW, Pearce LA. Sex, Stroke, and Atrial Fibrillation. Arch Neurol. 2012: 1-3. doi: 10. 1001/archneurol. 2012. 26911362172.
50. Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Behlouli H, Pilote L. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA. 2012;307(18): 1952-8. doi: 10. 1001/jama. 2012. 3490.
51. Sullivan RM, Zhang J, Zamba G, Lip GY, Olshansky B. Relation of Gender-Specific Risk of Ischemic Stroke in Patients With Atrial Fibrillation to Differences in Warfarin Anticoagulation Control (from AFFIRM). Am J Cardiol. 2012. doi: 10. 1016/j. amjcard. 2012. 08. 014.
52. Forster A, Gass A, Kern R, Wolf ME, Ottomeyer C, Zohsel K, et al. Gender differences in acute ischemic stroke: etiology, stroke patterns and response to thrombolysis. Stroke. 2009;40(7): 2428-32. doi: 10. 1161/STROKEAHA. 109. 548750.
53. Hall ED, Pazara KE, Linseman KL. Sex differences in postischemic neuronal necrosis in gerbils. J Cereb Blood Flow Metab. 1991;11(2): 292-8. doi: 10. 1038/jcbfm. 1991. 61.
54. Herson PS, Koerner IP, Hurn PD. Sex, sex steroids, and brain injury. Semin Reprod Med. 2009;27(3): 229-39. doi: 10. 1055/s-0029-1216276.
55. Hurn PD, Vannucci SJ, Hagberg H. Adult or perinatal brain injury: does sex matter? Stroke. 2005;36(2): 193-5. doi: 10. 1161/01. STR. 0000153064. 41332. f6.
56. Lewis DK, Thomas KT, Selvamani A, Sohrabji F. Age-related severity of focal ischemia in female rats is associated with impaired astrocyte function. Neurobiol Aging. 2012;33(6): 1123 e1-16. doi: 10. 1016/j. neurobiolaging. 2011. 11. 007.
57. Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, et al. Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience. 2010;170(2): 633-44. doi: 10. 1016/j. neuroscience. 2010. 07. 011.
58. Turtzo LC, McCullough LD. Sex differences in stroke. Cerebrovasc Dis. 2008;26(5): 462-74. doi: 10. 1159/000155983.
59. Manwani B, McCullough LD. Estrogen in ischaemic stroke: the debate continues. Eur J Neurol. 2012;19(10): 1276-7. doi: 10. 1111/j. 1468-1331. 2012. 03746. x.
60. Hurn PD, Macrae IM. Estrogen as a neuroprotectant in stroke. J Cereb Blood Flow Metab. 2000;20(4): 631-52. doi: 10. 1097/00004647-200004000-00001.
61. Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology. 2005;146(4): 1650-73. doi: 10. 1210/en. 2004-1142.
62. Arnold AP. Mouse models for evaluating sex chromosome effects that cause sex differences in non-gonadal tissues. J Neuroendocrinol. 2009;21(4): 377-86. doi: 10. 1111/j. 1365-2826. 2009. 01831. x.
63. Arnold AP, Chen X. What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol. 2009;30(1): 1-9. doi: 10. 1016/j. yfrne. 2008. 11. 001.
64. Cohen-Bendahan CC, van de Beek C, Berenbaum SA. Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings. Neurosci Biobehav Rev. 2005;29(2): 353-84. doi: 10. 1016/j. neubiorev. 2004. 11. 004.
65. Bakker J, De Mees C, Douhard Q, Balthazart J, Gabant P, Szpirer J, et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci. 2006;9(2): 220-6. doi: 10. 1038/nn1624.
66. Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav. 2009;55(5): 570-8. doi: 10. 1016/j. yhbeh. 2009. 03. 011.
67. McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab. 2003;14(5): 228-35.
68. Persky RW, Liu F, Xu Y, Weston G, Levy S, Roselli CE, et al. Neonatal testosterone exposure protects adult male rats from stroke. Neuroendocrinology. 2012. doi: 10. 1159/000343804.
69. Siegel C, Li J, Liu F, Benashski SE, McCullough LD. miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc Natl Acad Sci U S A. 2011;108(28): 11662-7. doi: 10. 1073/pnas. 1102635108.
70. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis. 2010;10(5): 338-49. doi: 10. 1016/S1473-3099(10)70049-9.
71. Chrousos GP. Stress and sex versus immunity and inflammation. Sci Signal. 2010;3(143). doi: 10. 1126/scisignal. 3143pe36. pe36.
72. Tian Y, Stamova B, Jickling GC, Liu D, Ander BP, Bushnell C, et al. Effects of gender on gene expression in the blood of ischemic stroke patients. J Cereb Blood Flow Metab. 2012;32(5): 780-91. doi: 10. 1038/jcbfm. 2011. 179.
73. Stamova B, Tian Y, Jickling G, Bushnell C, Zhan X, Liu D, et al. The X-chromosome has a different pattern of gene expression in women compared with men with ischemic stroke. Stroke. 2012;43(2): 326-34. doi: 10. 1161/STROKEAHA. 111. 629337.
74. Tian Y, Stamova B, Jickling GC, Xu H, Liu D, Ander BP, et al. Y chromosome gene expression in the blood of male patients with ischemic stroke compared with male controls. Gend Med. 2012;9(2): 68-75 e3. doi: 10. 1016/j. genm. 2012. 01. 005.
75. Sampson AK, Jennings GL, Chin-Dusting JP. Y are males so difficult to understand?: a case where "X" does not mark the spot. Hypertension. 2012;59(3): 525-31. doi: 10. 1161/HYPERTENSIONAHA. 111. 187880.
76. Manwani B, McCullough LD. Sexual dimorphism in ischemic stroke: lessons from the laboratory. Womens Health (Lond Engl). 2011;7(3): 319-39. doi: 10. 2217/whe. 11. 22.
77. Turtzo LC, Siegel C, McCullough LD. X chromosome dosage and the response to cerebral ischemia. J Neurosci. 2011;31(37): 13255-9.
78. Qureshi IA, Mehler MF. The emerging role of epigenetics in stroke: III. Neural stem cell biology and regenerative medicine. Arch Neurol. 2011;68(3): 294-302. doi: 10. 1001/archneurol. 2011. 6.
79. Qureshi IA, Mehler MF. The emerging role of epigenetics in stroke: II. RNA regulatory circuitry. Arch Neurol. 2010;67(12): 1435-41. doi: 10. 1001/archneurol. 2010. 300.
80. Qureshi IA, Mehler MF. Emerging role of epigenetics in stroke: part 1: DNA methylation and chromatin modifications. Arch Neurol. 2010;67(11): 1316-22. doi: 10. 1001/archneurol. 2010. 275.
81. Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol. 2008;8(1): 25-32. doi: 10. 1016/j. coph. 2007. 09. 001.
82. 2+ signaling, cell death and stroke. Trends Neurosci. 2006;29(2): 75-81. doi: 10. 1016/j. tins. 2005. 12. 001.
83. Beckman JS, Crow JP. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans. 1993;21(2): 330-4.
84. Crow JP, Beckman JS. Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. Adv Pharmacol. 1995;34: 17-43.
85. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, et al. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A. 2006;103(48): 18308-13. doi: 10. 1073/pnas. 0606526103.
86. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A. 2006;103(48): 18314-9. doi: 10. 1073/pnas. 0606528103.
87. Yuan M, Siegel C, Zeng Z, Li J, Liu F, McCullough LD. Sex differences in the response to activation of the poly(ADP-ribose) polymerase pathway after experimental stroke. Exp Neurol. 2009;217(1): 210-8. doi: 10. 1016/j. expneurol. 2009. 02. 012.
88. Reubold TF, Eschenburg S. A molecular view on signal transduction by the apoptosome. Cell Signal. 2012;24(7): 1420-5. doi: 10. 1016/j. cellsig. 2012. 03. 007.
89. Bushnell CD. Stroke and the female brain. Nat Clin Pract Neurol. 2008;4(1): 22-33. doi: 10. 1038/ncpneuro0686.
90. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13): 1293-304. doi: 10. 1056/NEJMoa050613.
91. Ment LR, Vohr BR, Makuch RW, Westerveld M, Katz KH, Schneider KC, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6): 832-4. doi: 10. 1016/j. jpeds. 2004. 07. 035.
92. Ohlsson A, Roberts RS, Schmidt B, Davis P, Moddeman D, Saigal S, et al. Male/female differences in indomethacin effects in preterm infants. J Pediatr. 2005;147(6): 860-2. doi: 10. 1016/j. jpeds. 2005. 07. 032.
93. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med. 2001;345(17): 1243-9. doi: 10. 1056/NEJMoa010534.
94. Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003;289(20): 2673-84. doi: 10. 1001/jama. 289. 20. 2673289/20/2673.
95. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7. doi: 10. 1002/14651858. CD004143. pub4.
96. Gaskins AJ, Wilchesky M, Mumford SL, Whitcomb BW, Browne RW, Wactawski-Wende J, et al. Endogenous reproductive hormones and C-reactive protein across the menstrual cycle: the BioCycle Study. Am J Epidemiol. 2012;175(5): 423-31. doi: 10. 1093/aje/kwr343.
97. Carcaillon L, Garcia-Garcia FJ, Tresguerres JA, Gutierrez Avila G, Kireev R, Rodriguez-Manas L. Higher levels of endogenous estradiol are associated with frailty in postmenopausal women from the toledo study for healthy aging. J Clin Endocrinol Metab. 2012;97(8): 2898-906. doi: 10. 1210/jc. 2012-1271jc. 2012-1271.
98. Lakoski SG, Herrington DM. Effects of hormone therapy on C-reactive protein and IL-6 in postmenopausal women: a review article. Climacteric. 2005;8(4): 317-26. doi: 10. 1080/13697130500345109.
99. Wander K, Brindle E, O'Connor KA. C-reactive protein across the menstrual cycle. Am J Phys Anthropol. 2008;136(2): 138-46. doi: 10. 1002/ajpa. 20785.
100. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345: e6409. doi: 10. 1136/bmj. e6409bmj. e6409.
101. Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci U S A. 2007;104(14): 6013-8. doi: 10. 1073/pnas. 0610394104.
102. Liu F, Benashski SE, Xu Y, Siegel M, McCullough LD. Effects of chronic and acute oestrogen replacement therapy in aged animals after experimental stroke. J Neuroendocrinol. 2012;24(2): 319-30. doi: 10. 1111/j. 1365-2826. 2011. 02248. x.
103. Lakshman R, Forouhi NG, Sharp SJ, Luben R, Bingham SA, Khaw KT, et al. Early age at menarche associated with cardiovascular disease and mortality. J Clin Endocrinol Metab. 2009;94(12): 4953-60. doi: 10. 1210/jc. 2009-1789.
104. Meseguer A, Puche C, Cabero A. Sex steroid biosynthesis in white adipose tissue. Horm Metab Res. 2002;34(11-12): 731-6. doi: 10. 1055/s-2002-38249.
105. Bulun SE, Simpson ER. Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab. 1994;78(2): 428-32.
106. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24): 2257-66. doi: 10. 1056/NEJMoa1111840.
107. Zakharova MY, Meyer RM, Brandy KR, Datta YH, Joseph MS, Schreiner PJ, et al. Risk factors for heart attack, stroke, and venous thrombosis associated with hormonal contraceptive use. Clin Appl Thromb Hemost. 2011;17(4): 323-31. doi: 10. 1177/1076029610368670.
108. Kittner SJ, Stern BJ, Feeser BR, Hebel R, Nagey DA, Buchholz DW, et al. Pregnancy and the risk of stroke. N Engl J Med. 1996;335(11): 768-74. doi: 10. 1056/NEJM199609123351102.
109. Tettenborn B. Stroke and pregnancy. Neurol Clin. 2012;30(3): 913-24. doi: 10. 1016/j. ncl. 2012. 06. 002.
110. Das A, Smith JA, Gibson C, Varma AK, Ray SK, Banik NL. Estrogen receptor agonists and estrogen attenuate TNF-alpha-induced apoptosis in VSC4. 1 motoneurons. J Endocrinol. 2011;208(2): 171-82. doi: 10. 1677/JOE-10-0338.
111. Tenenbaum M, Azab AN, Kaplanski J. Effects of estrogen against LPS-induced inflammation and toxicity in primary rat glial and neuronal cultures. J Endotoxin Res. 2007;13(3): 158-66. doi: 10. 1177/0968051907080428.
112. Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol. 2009;30(2): 201-11. doi: 10. 1016/j. yfrne. 2009. 04. 007.
113. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7(1): 42-59. doi: 10. 1007/s11481-011-9287-2.
114. Kamada M, Irahara M, Maegawa M, Ohmoto Y, Takeji T, Yasui T, et al. Postmenopausal changes in serum cytokine levels and hormone replacement therapy. Am J Obstet Gynecol. 2001;184(3): 309-14. doi: 10. 1067/mob. 2001. 109940.
115. Dziewulska D, Mossakowski MJ. Cellular expression of tumor necrosis factor a and its receptors in human ischemic stroke. Clin Neuropathol. 2003;22(1): 35-40.
116. Figiel I, Dzwonek K. TNFalpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res. 2007;1131(1): 17-28. doi: 10. 1016/j. brainres. 2006. 10. 095.
117. Dopp JM, Mackenzie-Graham A, Otero GC, Merrill JE. Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia. J Neuroimmunol. 1997;75(1-2): 104-12.
118. Bebo Jr BF, Linthicum DS. Expression of mRNA for 55-kDa and 75-kDa tumor necrosis factor (TNF) receptors in mouse cerebrovascular endothelium: effects of interleukin-1 beta, interferon-gamma and TNF-alpha on cultured cells. J Neuroimmunol. 1995;62(2): 161-7.
119. Tobinick E, Kim NM, Reyzin G, Rodriguez-Romanacce H, Depuy V. Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs. 2012. doi: 10. 1007/s40263-012-0013-2.
120. Lambertsen KL, Biber K, Finsen B. Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab. 2012;32(9): 1677-98. doi: 10. 1038/jcbfm. 2012. 88jcbfm201288.
121. Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull. 2012;87(1): 10-20. doi: 10. 1016/j. brainresbull. 2011. 10. 004.
122. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke. 1994;25(7): 1481-8.
123. Maddahi A, Kruse LS, Chen QW, Edvinsson L. The role of tumor necrosis factor-alpha and TNF-alpha receptors in cerebral arteries following cerebral ischemia in rat. J Neuroinflammation. 2011;8: 107. doi: 10. 1186/1742-2094-8-107.
124. Cui G, Wang H, Li R, Zhang L, Li Z, Wang Y, et al. Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke. J Neuroinflammation. 2012;9(1): 235. doi: 10. 1186/1742-2094-9-235.
125. Liao SL, Chen WY, Chen CJ. Estrogen attenuates tumor necrosis factor-alpha expression to provide ischemic neuroprotection in female rats. Neurosci Lett. 2002;330(2): 159-62.
126. Calippe B, Douin-Echinard V, Laffargue M, Laurell H, Rana-Poussine V, Pipy B, et al. Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol. 2008;180(12): 7980-8.
127. Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein. J Cereb Blood Flow Metab. 2012. doi: 10. 1038/jcbfm. 2012. 97jcbfm201297.
128. Matthews JR, Hay RT. Regulation of the DNA binding activity of NF-kappa B. Int J Biochem Cell Biol. 1995;27(9): 865-79.
129. Emmanouil M, Taoufik E, Tseveleki V, Vamvakas SS, Probert L. A role for neuronal NF-kappaB in suppressing neuroinflammation and promoting neuroprotection in the CNS. Adv Exp Med Biol. 2011;691: 575-81. doi: 10. 1007/978-1-4419-6612-4_60.
130. Rupec RA, Baeuerle PA. The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. Eur J Biochem. 1995;234(2): 632-40.
131. Dudek EJ, Shang F, Taylor A. H(2)O(2)-mediated oxidative stress activates NF-kappa B in lens epithelial cells. Free Radic Biol Med. 2001;31(5): 651-8.
132. Hoffmann A, Levchenko A, Scott ML, Baltimore D. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science. 2002;298(5596): 1241-5. doi: 10. 1126/science. 1071914298/5596/1241.
133. Carroll JE, Howard EF, Hess DC, Wakade CG, Chen Q, Cheng C. Nuclear factor-kappa B activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment. Brain Res Mol Brain Res. 1998;56(1-2): 186-91.
134. Schneider A, Martin-Villalba A, Weih F, Vogel J, Wirth T, Schwaninger M. NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med. 1999;5(5): 554-9. doi: 10. 1038/8432.
135. Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, et al. Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke. 2004;35(4): 987-91. doi: 10. 1161/01. STR. 0000120732. 45951. 26.
136. Culmsee C, Siewe J, Junker V, Retiounskaia M, Schwarz S, Camandola S, et al. Reciprocal inhibition of p53 and nuclear factor-kappaB transcriptional activities determines cell survival or death in neurons. J Neurosci. 2003;23(24): 8586-95.
137. Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull. 2001;55(3): 375-86.
138. Foehr ED, Lin X, O'Mahony A, Geleziunas R, Bradshaw RA, Greene WC. NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. J Neurosci. 2000;20(20): 7556-63.
139. Duckworth EA, Butler T, Collier L, Collier S, Pennypacker KR. NF-kappaB protects neurons from ischemic injury after middle cerebral artery occlusion in mice. Brain Res. 2006;1088(1): 167-75. doi: 10. 1016/j. brainres. 2006. 02. 103.
140. Sarnico I, Lanzillotta A, Benarese M, Alghisi M, Baiguera C, Battistin L, et al. NF-kappaB dimers in the regulation of neuronal survival. Int Rev Neurobiol. 2009;85: 351-62. doi: 10. 1016/S0074-7742(09)85024-1.
141. Ridder DA, Schwaninger M. NF-kappaB signaling in cerebral ischemia. Neuroscience. 2009;158(3): 995-1006. doi: 10. 1016/j. neuroscience. 2008. 07. 007.
142. Xing D, Oparil S, Yu H, Gong K, Feng W, Black J, et al. Estrogen modulates NFkappaB signaling by enhancing IkappaBalpha levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-beta. PLoS One. 2012;7(6): e36890. doi: 10. 1371/journal. pone. 0036890PONE-D-11-18299.
143. Lian H, Shim DJ, Gaddam SS, Rodriguez-Rivera J, Bitner BR, Pautler RG, et al. IkappaBalpha deficiency in brain leads to elevated basal neuroinflammation and attenuated response following traumatic brain injury: implications for functional recovery. Mol Neurodegener. 2012;7(1): 47. doi: 10. 1186/1750-1326-7-47.
144. Hoffmann A, Baltimore D. Circuitry of nuclear factor kappaB signaling. Immunol Rev. 2006;210: 171-86. doi: 10. 1111/j. 0105-2896. 2006. 00375. x.
145. Liu F, Lang J, Li J, Benashski SE, Siegel M, Xu Y, et al. Sex differences in the response to poly(ADP-ribose) polymerase-1 deletion and caspase inhibition after stroke. Stroke. 2011;42(4): 1090-6. doi: 10. 1161/STROKEAHA. 110. 594861.
146. Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH, et al. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011;3(1): 16. doi: 10. 1186/2040-7378-3-16.
147. Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009;29(4): 670-4. doi: 10. 1038/jcbfm. 2009. 3.
148. McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab. 2005;25(4): 502-12. doi: 10. 1038/sj. jcbfm. 9600059.
149. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419(6905): 367-74. doi: 10. 1038/nature01034nature01034.