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Cellular and Molecular Life Sciences

, Volume 76, Issue 3, pp 523–537 | Cite as

The regulatory role of Toll-like receptors after ischemic stroke: neurosteroids as TLR modulators with the focus on TLR2/4

  • Saeedeh Tajalli-Nezhad
  • Mohammad Karimian
  • Cordian Beyer
  • Mohammad Ali Atlasi
  • Abolfazl Azami TamehEmail author
Review
  • 213 Downloads

Abstract

Ischemic stroke is the most common cerebrovascular disease and considered as a worldwide leading cause of death. After cerebral ischemia, different pathophysiological processes including neuroinflammation, invasion and aggregation of inflammatory cells and up-regulation of cytokines occur simultaneously. In this respect, Toll-like receptors (TLRs) are the first identified important mediators for the activation of the innate immune system and are widely expressed in glial cells and neurons following brain trauma. TLRs are also able to interact with endogenous and exogenous molecules released during ischemia and can increase tissue damage. Particularly, TLR2 and TLR4 activate different downstream inflammatory signaling pathways. In addition, TLR signaling can alternatively play a role for endogenous neuroprotection. In this review, the gene and protein structures, common genetic polymorphisms of TLR2 and TLR4, TLR-related molecular pathways and their putative role after ischemic stroke are delineated. Furthermore, the relationship between neurosteroids and TLRs as neuroprotective mechanism is highlighted in the context of brain ischemia.

Keywords

Ischemic stroke Neurosteroids Toll-like receptors 

Notes

Acknowledgements

This work was supported by a grant (IR.KAUMS.REC. 1395. Grant no. 95086) from Kashan University of Medical Sciences.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Gentile NT, McIntosh TK (1993) Antagonists of excitatory amino acids and endogenous opioid peptides in the treatment of experimental central nervous system injury. Ann Emerg Med 22:1028–1034Google Scholar
  2. 2.
    Moghadam SE, Tameh AA, Vahidinia Z, Atlasi MA, Bafrani HH, Naderian H (2018) Neuroprotective effects of oxytocin hormone after an experimental stroke model and the possible role of Calpain-1. J Stroke Cerebrovasc Dis 27(3):724–732Google Scholar
  3. 3.
    Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI (1997) Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17:7415–7424Google Scholar
  4. 4.
    Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808Google Scholar
  5. 5.
    Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U et al (2011) Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 10:471–480Google Scholar
  6. 6.
    Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66:232–245Google Scholar
  7. 7.
    Wang Y-C, Lin S, Yang Q-W (2011) Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflamm 8:134Google Scholar
  8. 8.
    Crack PJ, Bray PJ (2007) Toll-like receptors in the brain and their potential roles in neuropathology. Immunol Cell Biol 85:476–480Google Scholar
  9. 9.
    Kaczorowski DJ, Mollen KP, Edmonds R, Billiar TR (2008) Early events in the recognition of danger signals after tissue injury. J Leukoc Biol 83:546–552Google Scholar
  10. 10.
    Wang Y, Ge P, Zhu Y (2013) TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediat Inflamm 2013:124614Google Scholar
  11. 11.
    Kipp M, Norkute A, Johann S, Lorenz L, Braun A, Hieble A et al (2008) Brain-region-specific astroglial responses in vitro after LPS exposure. J Mol Neurosci 35:235–243Google Scholar
  12. 12.
    Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9:429–439Google Scholar
  13. 13.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdörfer B, Giese T et al (2002) Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537Google Scholar
  14. 14.
    Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995Google Scholar
  15. 15.
    Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384Google Scholar
  16. 16.
    Matsushima N, Tanaka T, Enkhbayar P, Mikami T, Taga M, Yamada K et al (2007) Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate toll-like receptors. BMC Genom 8:124Google Scholar
  17. 17.
    Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD et al (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci USA 102:9577–9582Google Scholar
  18. 18.
    Gao W, Xiong Y, Li Q, Yang H (2017) Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol 8:508Google Scholar
  19. 19.
    Shichita T, Sakaguchi R, Suzuki M, Yoshimura A (2012) Post-ischemic inflammation in the brain. Front Immunol 3:132Google Scholar
  20. 20.
    Piccinini A, Midwood K (2010) DAMPening inflammation by modulating TLR signalling. Mediat Inflamm 2010:672395Google Scholar
  21. 21.
    Gürtler C, Bowie AG (2013) Innate immune detection of microbial nucleic acids. Trends Microbiol 21:413–420Google Scholar
  22. 22.
    Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461Google Scholar
  23. 23.
    Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34:269–281Google Scholar
  24. 24.
    Buchanan MM, Hutchinson M, Watkins LR, Yin H (2010) Toll-like receptor 4 in CNS pathologies. J Neurochem 114:13–27Google Scholar
  25. 25.
    Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58:253–263Google Scholar
  26. 26.
    Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP (2009) Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience 158:1007–1020Google Scholar
  27. 27.
    Carty M, Bowie AG (2011) Evaluating the role of Toll-like receptors in diseases of the central nervous system. Biochem Pharmacol 81:825–837Google Scholar
  28. 28.
    Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM (2003) Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol 24:528–533Google Scholar
  29. 29.
    Brodsky I, Medzhitov R (2007) Two modes of ligand recognition by TLRs. Cell 130:979–981Google Scholar
  30. 30.
    Uematsu S, Akira S (2008) Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol 183:1–20Google Scholar
  31. 31.
    Botos I, Segal DM, Davies DR (2011) The structural biology of Toll-like receptors. Structure 19:447–459Google Scholar
  32. 32.
    Flo TH, Halaas O, Torp S, Ryan L et al (2001) Differential expression of Toll-like receptor 2 in human cells. J Leukoc Biol 69:474–481Google Scholar
  33. 33.
    Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61:1013–1021Google Scholar
  34. 34.
    Farina C, Krumbholz M, Giese T, Hartmann G et al (2005) Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol 159:12–19Google Scholar
  35. 35.
    Rivest S (2003) Molecular insights on the cerebral innate immune system. Brain Behav Immun 17:13–19Google Scholar
  36. 36.
    Owens T, Babcock AA, Millward JM, Toft-Hansen H (2005) Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Brain Res Rev 48:178–184Google Scholar
  37. 37.
    Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83:711–730Google Scholar
  38. 38.
    Jack CS, Arbour N, Manusow J, Montgrain V et al (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330Google Scholar
  39. 39.
    Rosciszewski G, Cadena V, Murta V et al (2018) Toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells-2 (TREM-2) activation balance astrocyte polarization into a proinflammatory phenotype. Mol Neurobiol 55:3875–3888Google Scholar
  40. 40.
    Crocker SJ et al (2008) A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia. Glia 56:1187–1198Google Scholar
  41. 41.
    Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14Google Scholar
  42. 42.
    O’Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–564Google Scholar
  43. 43.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511Google Scholar
  44. 44.
    Takeda K, Akira S (eds) (2004) TLR signaling pathways. Semin Immunol 16:3–9Google Scholar
  45. 45.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801Google Scholar
  46. 46.
    Ostuni R, Zanoni I, Granucci F (2010) Deciphering the complexity of Toll-like receptor signaling. Cell Mol Life Sci 67:4109–4134Google Scholar
  47. 47.
    Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y et al (2008) Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 9:684–691Google Scholar
  48. 48.
    Xia Z-P, Sun L, Chen X, Pineda G, Jiang X, Adhikari A et al (2009) Direct activation of protein kinases by unanchored polyubiquitin chains. Nature 461:114–119Google Scholar
  49. 49.
    Medzhitov R (2001) Toll-like receptors and innate immunity. Rev Immunol 1:135–145Google Scholar
  50. 50.
    Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820Google Scholar
  51. 51.
    Guijarro C, Egido J (2001) Transcription factor-κB (NF-κB) and renal disease. Kidney Int 59:415–424Google Scholar
  52. 52.
    Nozaki K, Nishimura M, Hashimoto N (2001) Mitogen-activated protein kinases and cerebral ischemia. Mol Neurobiol 23:1–19Google Scholar
  53. 53.
    Nito C, Kamada H, Endo H, Narasimhan P, Lee Y-S, Chan PH (2012) Involvement of mitogen-activated protein kinase pathways in expression of the water channel protein aquaporin-4 after ischemia in rat cortical astrocytes. J Neurotrauma 29:2404–2412Google Scholar
  54. 54.
    Yasukawa H, Sasaki A, Yoshimura A (2000) Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18:143–164Google Scholar
  55. 55.
    Nakagawa R, Naka T, Tsutsui H, Fujimoto M et al (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17:677–687Google Scholar
  56. 56.
    Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465Google Scholar
  57. 57.
    Starczynowski DT, Karsan A (2010) Innate immune signaling in the myelodysplastic syndromes. Hematol Oncol Clin N Am 24:343–359Google Scholar
  58. 58.
    Klesney-Tait J, Turnbull IR, Colonna M (2006) The TREM receptor family and signal integration. Nat Immunol 7:1266Google Scholar
  59. 59.
    Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164:4991–4995Google Scholar
  60. 60.
    Nathan C, Ding A (2001) TREM-1: a new regulator of innate immunity in sepsis syndrome. Nat Med 7:530Google Scholar
  61. 61.
    Klesney-Tait J, Colonna M (2007) Uncovering the TREM-1-TLR connection. Am J Physiol Lung Cell Mol Physiol 293:L1374–L1376Google Scholar
  62. 62.
    Ornatowska M, Azim AC, Wang X, Christman JW et al (2007) Functional genomics of silencing TREM-1 on TLR4 signaling in macrophages. Am J Physiol Lung Cell Mol Physiol 293:L1377–L1384Google Scholar
  63. 63.
    Golovkin A, Matveeva VG, Kudryavtsev IV, Chernova MN et al (2013) Perioperative dynamics of TLR2, TLR4, and TREM-1 expression in monocyte subpopulations in the setting of on-pump coronary artery bypass surgery. ISRN Inflamm 2013:817901Google Scholar
  64. 64.
    Marsh BJ, Stenzel-Poore MP (2008) Toll-like receptors: novel pharmacological targets for the treatment of neurological diseases. Curr Opin Pharmacol 8:8–13Google Scholar
  65. 65.
    Marsh BJ, Stevens SL, Hunter B, Stenzel-Poore MP (2009) Inflammation and the emerging role of the toll-like receptor system in acute brain ischemia. Stroke 40:S34–S37Google Scholar
  66. 66.
    Tang S-C, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG et al (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci 104:13798–13803Google Scholar
  67. 67.
    Chen S, Wong MH, Schulte DJ, Arditi M, Michelsen KS (2007) Differential expression of Toll-like receptor 2 (TLR2) and responses to TLR2 ligands between human and murine vascular endothelial cells. J Endotoxin Res 13:281–296Google Scholar
  68. 68.
    Ziegler G, Harhausen D, Schepers C, Hoffmann O, Röhr C, Prinz V et al (2007) TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 359:574–579Google Scholar
  69. 69.
    Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G (2011) Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. J Cereb Blood Flow Metab 31:757–766Google Scholar
  70. 70.
    Yang Q-W, Lu F-L, Zhou Y, Wang L, Zhong Q, Lin S et al (2011) HMBG1 mediates ischemia—reperfusion injury by TRIF-adaptor independent toll-like receptor 4 signaling. J Cereb Blood Flow Metab 31:593–605Google Scholar
  71. 71.
    Yang Q-W, Wang J-Z, Li J-C, Zhou Y, Qi-Zhong LuF-L et al (2010) High-mobility group protein box-1 and its relevance to cerebral ischemia. J Cereb Blood Flow Metab 30:243–254Google Scholar
  72. 72.
    Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI et al (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938Google Scholar
  73. 73.
    Muhammad S, Barakat W, Stoyanov S, Murikinati S, Yang H, Tracey KJ et al (2008) The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci 28:12023–12031Google Scholar
  74. 74.
    Liu K, Mori S, Takahashi HK, Tomono Y, Wake H, Kanke T et al (2007) Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J 21:3904–3916Google Scholar
  75. 75.
    Patenaude A, Murthy M, Mirault M-E (2005) Emerging roles of thioredoxin cycle enzymes in the central nervous system. Cell Mol Life Sci CMLS 62:1063–1080Google Scholar
  76. 76.
    Rashidian J, Rousseaux MW, Venderova K, Qu D, Callaghan SM, Phillips M et al (2009) Essential role of cytoplasmic cdk5 and Prx2 in multiple ischemic injury models, in vivo. J Neurosci 29:12497–12505Google Scholar
  77. 77.
    Lehnardt S, Lehmann S, Kaul D, Tschimmel K, Hoffmann O, Cho S et al (2007) Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol 190:28–33Google Scholar
  78. 78.
    Lv M, Liu Y, Zhang J, Sun L, Liu Z, Zhang S et al (2011) Roles of inflammation response in microglia cell through Toll-like receptors 2/interleukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience 176:162–172Google Scholar
  79. 79.
    Abe T, Shimamura M, Jackman K, Kurinami H, Anrather J, Zhou P et al (2010) Key role of CD36 in Toll-like receptor 2 signaling in cerebral ischemia. Stroke 41:898–904Google Scholar
  80. 80.
    Brea D, Sobrino T, Rodríguez-Yáñez M, Ramos-Cabrer P, Agulla J, Rodríguez-González R et al (2011) Toll-like receptors 7 and 8 expression is associated with poor outcome and greater inflammatory response in acute ischemic stroke. Clin Immunol 139:193–198Google Scholar
  81. 81.
    Hyakkoku K, Hamanaka J, Tsuruma K, Shimazawa M, Tanaka H, Uematsu S et al (2010) Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 171:258–267Google Scholar
  82. 82.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413:732–738Google Scholar
  83. 83.
    Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27:13033–13041Google Scholar
  84. 84.
    Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA et al (2010) Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci 107:15625–15630Google Scholar
  85. 85.
    Wang P-F, Xiong X-Y, Chen J, Wang Y-C, Duan W, Yang Q-W (2015) Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment. J Neuroinflamm 12:80Google Scholar
  86. 86.
    Hayakawa K, Qiu J, Lo EH (2010) Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. Ann N Y Acad Sci 1207:50–57Google Scholar
  87. 87.
    Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe C-U, Siler DA et al (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40:1849–1857Google Scholar
  88. 88.
    Zhang J, Takahashi HK, Liu K, Wake H, Liu R, Maruo T et al (2011) Anti-high mobility group box-1 monoclonal antibody protects the blood–brain barrier from ischemia-induced disruption in rats. Stroke 42:1420–1428Google Scholar
  89. 89.
    C-x Cao, Q-w Yang, F-l Lv, Cui J, H-b Fu, J-z Wang (2007) Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353:509–514Google Scholar
  90. 90.
    Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115:1599–1608Google Scholar
  91. 91.
    Tang S-C, Lathia JD, Selvaraj PK, Jo D-G, Mughal MR, Cheng A et al (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213:114–121Google Scholar
  92. 92.
    Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I (2008) Toll-like receptor 4 is involved in subacute stress–induced neuroinflammation and in the worsening of experimental stroke. Stroke 39:1314–1320Google Scholar
  93. 93.
    Kilic U, Kilic E, Matter CM, Bassetti CL, Hermann DM (2008) TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 31:33–40Google Scholar
  94. 94.
    Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule J-L et al (2008) Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab 28:1040–1047Google Scholar
  95. 95.
    Nalamolu KR, Smith NJ, Chelluboina B, Klopfenstein JD et al (2018) Prevention of the severity of post-ischemic inflammation and brain damage by simultaneous knockdown of Toll-like receptors 2 and 4. Neuroscience 373:82–91Google Scholar
  96. 96.
    Song Y, Liu H, Long L, Zhang N, Liu Y (2015) TLR4 rs1927911, but Not TLR2 rs5743708, is associated with atherosclerotic cerebral infarction in the Southern Han population: a case–control study. Medicine 94:e381Google Scholar
  97. 97.
    Lin Y-C, Chang Y-M, Yu J-M, Yen J-H, Chang J-G, Hu C-J (2005) Toll-like receptor 4 gene C119A but not Asp299Gly polymorphism is associated with ischemic stroke among ethnic Chinese in Taiwan. Atherosclerosis 180:305–309Google Scholar
  98. 98.
    Ioana M, Ferwerda B, Plantinga T, Stappers M, Oosting M, McCall M et al (2012) Different patterns of Toll-like receptor 2 polymorphisms in populations of various ethnic and geographic origins. Infect Immun 80:1917–1922Google Scholar
  99. 99.
    Zhou L, Zheng D, Wang S, Zhu J, Jia Y, Sun D et al (2016) Genetic association of Toll-like receptor 4 gene and coronary artery disease in a Chinese Han population. SpringerPlus 5:1533Google Scholar
  100. 100.
    Ebrahimi A, Colagar AH, Karimian M (2017) Association of human methionine synthase-A2756G transition with prostate cancer: a case–control study and in silico analysis. Acta Med Iran 55:297–303Google Scholar
  101. 101.
    Zamani-Badi T, Nikzad H, Karimian M (2018) IL-1RA VNTR and IL-1α 4845G > T polymorphisms and risk of idiopathic male infertility in Iranian men: a case–control study and an in silico analysis. Andrologia 3:e13081Google Scholar
  102. 102.
    Sabarinathan R, Tafer H, Seemann SE, Hofacker IL, Stadler PF, Gorodkin J (2013) RNAsnp: efficient detection of local RNA secondary structure changes induced by SNPs. Hum Mutat 34:546–556Google Scholar
  103. 103.
    Zamani-Badi T, Karimian M, Azami-Tameh A, Nikzad H (2017) Association of C3953T transition in interleukin 1β gene with idiopathic male infertility in an Iranian population. Hum Fertil 3:1–7Google Scholar
  104. 104.
    Karimian M, Aftabi Y, Mazoochi T, Babaei F et al (2018) Survivin polymorphisms and susceptibility to prostate cancer: a genetic association study and an in silico analysis. EXCLI J 17:479Google Scholar
  105. 105.
    Salimi S, Keshavarzi F, Mohammadpour-Gharehbagh A, Moodi M et al (2017) Polymorphisms of the folate metabolizing enzymes: association with SLE susceptibility and in silico analysis. Gene 637:161–172Google Scholar
  106. 106.
    Tameh AA, Karimian M, Zare-Dehghanani Z, Aftabi Y et al (2018) Role of steroid therapy after ischemic stroke by N-methyl-d-aspartate receptor gene regulation. J Stroke Cerebrovasc Dis 27:3066–3075Google Scholar
  107. 107.
    Nejati M, Atlasi MA, Karimian M, Nikzad H et al (2018) Lipoprotein lipase gene polymorphisms as risk factors for stroke: a computational and meta-analysis. Iran J Basic Med Sci 21:701–708Google Scholar
  108. 108.
    Reumers J, Schymkowitz J, Ferkinghoff-Borg J, Stricher F, Serrano L, Rousseau F (2005) SNPeffect: a database mapping molecular phenotypic effects of human non-synonymous coding SNPs. Nucleic Acids Res 33:D527–D532Google Scholar
  109. 109.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249Google Scholar
  110. 110.
    Bromberg Y, Rost B (2007) SNAP: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Res 35:3823–3835Google Scholar
  111. 111.
    Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081Google Scholar
  112. 112.
    De Baets G, Van Durme J, Reumers J, Maurer-Stroh S, Vanhee P, Dopazo J et al (2011) SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants. Nucleic Acids Res 40:D935–D939Google Scholar
  113. 113.
    Capriotti E, Calabrese R, Fariselli P, Martelli PL, Altman RB, Casadio R (2013) WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation. BMC Genom 14:S6Google Scholar
  114. 114.
    Compagnone NA, Mellon SH (2000) Neurosteroids: biosynthesis and function of these novel neuromodulators. Front Neuroendocrinol 21:1–56Google Scholar
  115. 115.
    Rupprecht R, Holsboer F (1999) Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 22:410–416Google Scholar
  116. 116.
    Hua F, Wang J, Ishrat T, Wei W, Atif F, Sayeed I et al (2011) Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone. J Neuroinflamm 8:42Google Scholar
  117. 117.
    Lobo RA, Pinkerton JV, Gass ML, Dorin MH, Ronkin S, Pickar JH et al (2009) Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril 92:1025–1038Google Scholar
  118. 118.
    Carwile E, Wagner AK, Crago E, Alexander SA (2009) Estrogen and stroke: a review of the current literature. J Neurosci Nurs 41:18–25Google Scholar
  119. 119.
    Roof RL, Hall ED (2000) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 17:367–388Google Scholar
  120. 120.
    Baulieu E-E, Schumacher M (2000) Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Steroids 65:605–612Google Scholar
  121. 121.
    Johann S, Beyer C (2013) Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia. J Steroid Biochem Mol Biol 137:71–81Google Scholar
  122. 122.
    Ritzel RM, Capozzi LA, McCullough LD (2013) Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm Behav 63:238–253Google Scholar
  123. 123.
    Suzuki S, Brown CM, Wise PM (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30:201–211Google Scholar
  124. 124.
    Zhang Q-G, Raz L, Wang R, Han D, De Sevilla L, Yang F et al (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activation. J Neurosci 29:13823–13836Google Scholar
  125. 125.
    Herson PS, Koerner IP, Hurn PD (2009) Sex, sex steroids, and brain injury. Semin Reprod Med 27:229–239Google Scholar
  126. 126.
    Fu J, Xue R, Gu J, Xiao Y, Zhong H, Pan X et al (2013) Neuroprotective effect of calcitriol on ischemic/reperfusion injury through the NR3A/CREB pathways in the rat hippocampus. Mol Med Rep 8:1708–1714Google Scholar
  127. 127.
    Brewer LD, Thibault V, Chen K-C, Langub MC, Landfield PW, Porter NM (2001) Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci 21:98–108Google Scholar
  128. 128.
    Kalueff A, Eremin K, Tuohimaa P (2004) Mechanisms of neuroprotective action of vitamin D3. Biochemistry (Moscow) 69:738–741Google Scholar
  129. 129.
    Manthey D, Behl C (2006) From structural biochemistry to expression profiling: neuroprotective activities of estrogen. Neuroscience 138:845–850Google Scholar
  130. 130.
    Strom JO, Theodorsson A, Theodorsson E (2009) Dose-related neuroprotective versus neurodamaging effects of estrogens in rat cerebral ischemia: a systematic analysis. J Cereb Blood Flow Metab 29:1359–1372Google Scholar
  131. 131.
    Strom JO, Theodorsson A, Theodorsson E (2011) Mechanisms of estrogens’ dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia. Int J Mol Sci 12:1533–1562Google Scholar
  132. 132.
    Kipp M, Karakaya S, Pawlak J, Araujo-Wright G, Arnold S, Beyer C (2006) Estrogen and the development and protection of nigrostriatal dopaminergic neurons: concerted action of a multitude of signals, protective molecules, and growth factors. Front Neuroendocrinol 27:376–390Google Scholar
  133. 133.
    Zhang Q-G, Wang R, Tang H, Dong Y, Chan A, Sareddy GR et al (2014) Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus. Mol Cell Endocrinol 389:84–91Google Scholar
  134. 134.
    Jover-Mengual T, Castelló-Ruiz M, Burguete MC, Jorques M, López-Morales MA, Aliena-Valero A et al (2017) Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: a comparative study with 17β-estradiol. J Steroid Biochem Mol Biol 171:296–304Google Scholar
  135. 135.
    Gibson CL, Gray LJ, Murphy SP, Bath PM (2006) Estrogens and experimental ischemic stroke: a systematic review. J Cereb Blood Flow Metab 26:1103–1113Google Scholar
  136. 136.
    Scharfman HE, MacLusky NJ (2006) Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS. Front Neuroendocrinol 27:415–435Google Scholar
  137. 137.
    Marks MA, Gravitt PE, Burk RD, Studentsov Y, Farzadegan H, Klein SL (2010) Progesterone and 17β-estradiol enhance regulatory responses to human papillomavirus type 16 virus-like particles in peripheral blood mononuclear cells from healthy women. Clin Vaccine Immunol 17:609–617Google Scholar
  138. 138.
    Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7:97Google Scholar
  139. 139.
    Xu Y, Sheng H, Bao Q, Wang Y, Lu J, Ni X (2016) NLRP3 inflammasome activation mediates estrogen deficiency-induced depression-and anxiety-like behavior and hippocampal inflammation in mice. Brain Behav Immun 56:175–186Google Scholar
  140. 140.
    Cordeau P, Lalancette-Hébert M, Weng YC, Kriz J (2016) Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice. Neurobiol Aging 40:50–60Google Scholar
  141. 141.
    Behl C (2002) Oestrogen as a neuroprotective hormone. Nat Rev Neurosci 3:433–442Google Scholar
  142. 142.
    Dubal DB, Rau SW, Shughrue PJ, Zhu H, Yu J, Cashion AB et al (2006) Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERα in estradiol-mediated protection against delayed cell death. Endocrinology 147:3076–3084Google Scholar
  143. 143.
    Rusa R, Alkayed NJ, Crain BJ, Traystman RJ, Kimes AS, London ED et al (1999) 17β-Estradiol reduces stroke injury in estrogen-deficient female animals. Stroke 30:1665–1670Google Scholar
  144. 144.
    Kurebayashi S, Miyashita Y, Hirose T, Kasayama S, Akira S, Kishimoto T (1997) Characterization of mechanisms of interleukin-6 gene repression by estrogen receptor. J Steroid Biochem Mol Biol 60:11–17Google Scholar
  145. 145.
    Stein B, Yang MX (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol 15:4971–4979Google Scholar
  146. 146.
    Ghisletti S, Meda C, Maggi A, Vegeto E (2005) 17β-estradiol inhibits inflammatory gene expression by controlling NF-κB intracellular localization. Mol Cell Biol 25:2957–2968Google Scholar
  147. 147.
    Koellhoffer EC, McCullough LD (2013) The effects of estrogen in ischemic stroke. Transl Stroke Res 4:390–401Google Scholar
  148. 148.
    Liao SL, Chen WY, Chen CJ (2002) Estrogen attenuates tumor necrosis factor-α expression to provide ischemic neuroprotection in female rats. Neurosci Lett 330:159–162Google Scholar
  149. 149.
    Wen Y, Yang S, Liu R, Perez E, Yi KD, Koulen P et al (2004) Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia. Brain Res 1008:147–154Google Scholar
  150. 150.
    Calippe B, Douin-Echinard V, Laffargue M, Laurell H, Rana-Poussine V, Pipy B et al (2008) Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol 180:7980–7988Google Scholar
  151. 151.
    Chiappetta O, Gliozzi M, Siviglia E, Amantea D, Morrone LA, Berliocchi L et al (2007) Evidence to implicate early modulation of interleukin-1β expression in the neuroprotection afforded by 17β-estradiol in male rats undergone transient middle cerebral artery occlusion. Int Rev Neurobiol 82:357–372Google Scholar
  152. 152.
    Petrone AB, Simpkins JW, Barr TL (2014) 17β-Estradiol and inflammation: implications for ischemic stroke. Aging Dis 5:340–345Google Scholar
  153. 153.
    Dominguez R, Liu R, Baudry M (2007) 17-β-Estradiol-mediated activation of extracellular-signal regulated kinase, phosphatidylinositol 3-kinase/protein kinase B-Akt and N-methyl-d-aspartate receptor phosphorylation in cortical synaptoneurosomes. J Neurochem 101:232–240Google Scholar
  154. 154.
    Pinceti E (2016) Consequences of estrogen receptor beta phosphorylation in the aged female brain and heart. Loyola University Chicago, ChicagoGoogle Scholar
  155. 155.
    Stein DG (2013) A clinical/translational perspective: can a developmental hormone play a role in the treatment of traumatic brain injury? Horm Behav 63:291–300Google Scholar
  156. 156.
    Wright DW, Bauer ME, Hoffman SW, Stein DG (2001) Serum progesterone levels correlate with decreased cerebral edema after traumatic brain injury in male rats. J Neurotrauma 18:901–909Google Scholar
  157. 157.
    O’Connor CA, Cernak I, Vink R (2005) Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats. Brain Res 1062:171–174Google Scholar
  158. 158.
    Pettus EH, Wright DW, Stein DG, Hoffman SW (2005) Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res 1049:112–119Google Scholar
  159. 159.
    Guo Q, Sayeed I, Baronne LM, Hoffman SW, Guennoun R, Stein DG (2006) Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp Neurol 198:469–478Google Scholar
  160. 160.
    Leonelli E, Bianchi R, Cavaletti G, Caruso D, Crippa D, Garcia-Segura L et al (2007) Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 144:1293–1304Google Scholar
  161. 161.
    VanLandingham JW, Cekic M, Cutler SM, Hoffman SW, Washington ER, Johnson SJ et al (2008) Progesterone and its metabolite allopregnanolone differentially regulate hemostatic proteins after traumatic brain injury. J Cereb Blood Flow Metab 28:1786–1794Google Scholar
  162. 162.
    Loane DJ, Faden AI (2010) Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 31:596–604Google Scholar
  163. 163.
    Brinton RD, Thompson RF, Foy MR, Baudry M, Wang J, Finch CE et al (2008) Progesterone receptors: form and function in brain. Front Neuroendocrinol 29:313–339Google Scholar
  164. 164.
    Mani S (2008) Progestin receptor subtypes in the brain: the known and the unknown. Endocrinology 149:2750–2756Google Scholar
  165. 165.
    Singh M, Su C (2013) Progesterone and neuroprotection. Horm Behav 63:284–290Google Scholar
  166. 166.
    Li X, Zhang J, Zhu X, Wang P, Wang X, Li D (2015) Progesterone reduces inflammation and apoptosis in neonatal rats with hypoxic ischemic brain damage through the PI3K/Akt pathway. Int J Clin Exp Med 8:8197–8203Google Scholar
  167. 167.
    Wang Z, Zuo G, Shi X-Y, Zhang J, Fang Q, Chen G (2011) Progesterone administration modulates cortical TLR4/NF-κB signaling pathway after subarachnoid hemorrhage in male rats. Mediat Inflamm 2011:848309Google Scholar
  168. 168.
    Lei B, Mace B, Dawson HN, Warner DS, Laskowitz DT, James ML (2014) Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia. PLoS One 9:e103969Google Scholar
  169. 169.
    Chen G, Shi J, Jin W, Wang L, Xie W, Sun J et al (2008) Progesterone administration modulates TLRS/NF-κB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci 38:65–74Google Scholar
  170. 170.
    Hardy DB, Janowski BA, Chen C-C, Mendelson CR (2008) Progesterone receptor inhibits aromatase and inflammatory response pathways in breast cancer cells via ligand-dependent and ligand-independent mechanisms. Mol Endocrinol 22:1812–1824Google Scholar
  171. 171.
    He J, Evans C-O, Hoffman SW, Oyesiku NM, Stein DG (2004) Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp Neurol 189:404–412Google Scholar
  172. 172.
    Ishrat T, Sayeed I, Atif F, Hua F, Stein DG (2010) Progesterone and allopregnanolone attenuate blood–brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases. Exp Neurol 226:183–190Google Scholar
  173. 173.
    Jones NC, Constantin D, Prior MJ, Morris PG, Marsden CA, Murphy S (2005) The neuroprotective effect of progesterone after traumatic brain injury in male mice is independent of both the inflammatory response and growth factor expression. Eur J Neurosci 21:1547–1554Google Scholar
  174. 174.
    Toung TJ, Chen T-Y, Littleton-Kearney MT, Hurn PD, Murphy SJ (2004) Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats. J Cereb Blood Flow Metab 24:1160–1166Google Scholar
  175. 175.
    Lorenz L, Dang J, Misiak M, Tameh Abolfazl A, Beyer C, Kipp M (2009) Combined 17β-oestradiol and progesterone treatment prevents neuronal cell injury in cortical but not midbrain neurones or neuroblastoma cells. J Neuroendocrinol 21:841–849Google Scholar
  176. 176.
    Habib P, Dang J, Slowik A, Victor M, Beyer C (2014) Hypoxia-induced gene expression of aquaporin-4, cyclooxygenase-2 and hypoxia-inducible factor 1α in rat cortical astroglia is inhibited by 17β-estradiol and progesterone. Neuroendocrinology 99:156–167Google Scholar
  177. 177.
    Dang J, Mitkari B, Kipp M, Beyer C (2011) Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. Brain Behav Immun 25:715–726Google Scholar
  178. 178.
    Vahidinia Z, Alipour N, Atlasi MA, Naderian H, Beyer C, Azami Tameh A (2017) Gonadal steroids block the calpain-1-dependent intrinsic pathway of apoptosis in an experimental rat stroke model. Neurol Res 39:54–64Google Scholar
  179. 179.
    Slowik A, Beyer C (2015) Inflammasomes are neuroprotective targets for sex steroids. J Steroid Biochem Mol Biol 153:135–143Google Scholar
  180. 180.
    Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A (2016) Poststroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology 103:460–475Google Scholar
  181. 181.
    Hoffmann S, Beyer C, Zendedel A (2015) Comparative analysis of gonadal steroid-mediated neuroprotection after transient focal ischemia in rats: route of application and substrate composition. J Mol Neurosci 56:12–16Google Scholar
  182. 182.
    Schumacher M, Denier C, Oudinet JP, Adams D et al (2016) Progesterone neuroprotection: the background of clinical trial failure. J Steroid Biochem Mol Biol 160:53–66Google Scholar
  183. 183.
    Goss CW, Hoffman SW, Stein DG (2003) Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response study. Pharmacol Biochem Behav 76:231–242Google Scholar
  184. 184.
    Galani R, Hoffman SW, Stein DG (2001) Effects of the duration of progesterone treatment on the resolution of cerebral edema induced by cortical contusions in rats. Restor Neurol Neurosci 18:161–166Google Scholar
  185. 185.
    Shear DA, Galani R, Hoffman SW, Stein DG (2002) Progesterone protects against necrotic damage and behavioral abnormalities caused by traumatic brain injury. Exp Neurol 178:59–67Google Scholar
  186. 186.
    Eelen G, Verlinden L, Van Camp M, Van Hummelen P, Marchal K, De Moor B et al (2004) The effects of 1α, 25-dihydroxyvitamin D3 on the expression of DNA replication genes. J Bone Miner Res 19:133–146Google Scholar
  187. 187.
    Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C (2010) Vitamin D: modulator of the immune system. Curr Opin Pharmacol 10:482–496Google Scholar
  188. 188.
    Yuan J, Guo X, Liu Z, Zhao X, Feng Y, Song S et al (2018) Vitamin D receptor activation influences the ERK pathway and protects against neurological deficits and neuronal death. Int J Mol Med 41:364–372Google Scholar
  189. 189.
    Farach-Carson MC, Nemere I (2003) Membrane receptors for vitamin D steroid hormones: potential new drug targets. Curr Drug Targets 4:67–76Google Scholar
  190. 190.
    De Bosscher K, Vanden Berghe W, Haegeman G (2006) Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 25:6868–6886Google Scholar
  191. 191.
    Norman AW, Nemere I, Zhou L-X, Bishop JE, Lowe KE, Maiyar AC et al (1992) 1,25 (OH) 2-vitamin D3, a steroid hormone that produces biologic effects via both genomic and nongenomic pathways. J Steroid Biochem Mol Biol 41:231–240Google Scholar
  192. 192.
    Calton EK, Keane KN, Newsholme P, Soares MJ (2015) The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PLoS One 10:e0141770Google Scholar
  193. 193.
    Yin K, Agrawal DK (2014) Vitamin D and inflammatory diseases. J Inflamm Res 7:69–87Google Scholar
  194. 194.
    Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC (2013) Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein. J Biol Chem 288:19450–19458Google Scholar
  195. 195.
    Vuolo L, Di Somma C, Faggiano A, Colao A (2012) Vitamin D and cancer. Front Endocrinol (Lausanne) 3:58Google Scholar
  196. 196.
    Sanchez-Niño M-D, Bozic M, Córdoba-Lanús E, Valcheva P, Gracia O, Ibarz M et al (2011) Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathy. Am J Physiol Renal Physiol 302:F647–F657Google Scholar
  197. 197.
    Mutt SJ, Hyppönen E, Saarnio J, Järvelin M-R, Herzig K-H (2014) Vitamin D and adipose tissue—more than storage. Front Physiol 5:228Google Scholar
  198. 198.
    Won S, Sayeed I, Peterson BL, Wali B, Kahn JS, Stein DG (2015) Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways. PLoS One 10:e0122821Google Scholar
  199. 199.
    Chen Y, Liu W, Sun T, Huang Y, Wang Y, Deb DK et al (2013) 1,25-Dihydroxyvitamin D promotes negative feedback regulation of TLR signaling via targeting MicroRNA-155–SOCS1 in macrophages. J Immunol 190:3687–3695Google Scholar
  200. 200.
    Sadeghi K, Wessner B, Laggner U, Ploder M, Tamandl D, Friedl J et al (2006) Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 36:361–370Google Scholar
  201. 201.
    Di Rosa M, Malaguarnera G, De Gregorio C, Palumbo M, Nunnari G, Malaguarnera L (2012) Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages. Cell Immunol 280:36–43Google Scholar
  202. 202.
    Kamen DL, Tangpricha V (2010) Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med 88:441–450Google Scholar
  203. 203.
    Kawai T, Akira S (eds) (2007) TLR signaling. Semin Immunol 19:24–32Google Scholar
  204. 204.
    Turetsky A, Goddeau RP, Henninger N (2015) Low serum vitamin D is independently associated with larger lesion volumes after ischemic stroke. J Stroke Cerebrovasc Dis 24:1555–1563Google Scholar
  205. 205.
    Balden R, Selvamani A, Sohrabji F (2012) Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats. Endocrinology 153:2420–2435Google Scholar
  206. 206.
    Dickie LJ, Church LD, Coulthard LR, Mathews RJ, Emery P, McDermott MF (2010) Vitamin D3 down-regulates intracellular Toll-like receptor 9 expression and Toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatology 49:1466–1471Google Scholar
  207. 207.
    Tang H, Hua F, Wang J, Yousuf S, Atif F, Sayeed I et al (2015) Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury. Brain Inj 17:1–10Google Scholar
  208. 208.
    Atif F, Yousuf S, Sayeed I, Ishrat T, Hua F, Stein DG (2013) Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection. Neuropharmacology 67:78–87Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Saeedeh Tajalli-Nezhad
    • 1
  • Mohammad Karimian
    • 1
  • Cordian Beyer
    • 2
  • Mohammad Ali Atlasi
    • 1
  • Abolfazl Azami Tameh
    • 1
    Email author
  1. 1.Anatomical Sciences Research CenterKashan University of Medical SciencesKashanIran
  2. 2.Institute of Neuroanatomy, Faculty of MedicineRWTH Aachen UniversityAachenGermany

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