Molecular Neurobiology

, Volume 53, Issue 1, pp 143–154 | Cite as

Immunomodulatory Effect of Toll-Like Receptor-3 Ligand Poly I:C on Cortical Spreading Depression

  • Amir Ghaemi
  • Azadeh Sajadian
  • Babak Khodaie
  • Ahmad Ali Lotfinia
  • Mahmoud Lotfinia
  • Afsaneh Aghabarari
  • Maryam Khaleghi Ghadiri
  • Sven Meuth
  • Ali GorjiEmail author


The release of inflammatory mediators following cortical spreading depression (CSD) is suggested to play a role in pathophysiology of CSD-related neurological disorders. Toll-like receptors (TLR) are master regulators of innate immune function and involved in the activation of inflammatory responses in the brain. TLR3 agonist poly I:C exerts anti-inflammatory effect and prevents cell injury in the brain. The aim of the present study was to examine the effect of systemic administration of poly I:C on the release of cytokines (TNF-α, IFN-γ, IL-4, TGF-β1, and GM-CSF) in the brain and spleen, splenic lymphocyte proliferation, expression of GAD65, GABAAα, GABAAβ as well as Hsp70, and production of dark neurons after induction of repetitive CSD in juvenile rats. Poly I:C significantly attenuated CSD-induced production of TNF-α and IFN-γ in the brain as well as TNF-α and IL-4 in the spleen. Poly I:C did not affect enhancement of splenic lymphocyte proliferation after CSD. Administration of poly I:C increased expression of GABAAα, GABAAβ as well as Hsp70 and decreased expression of GAD65 in the entorhinal cortex compared to CSD-treated tissues. In addition, poly I:C significantly prevented production of CSD-induced dark neurons. The data indicate neuroprotective and anti-inflammatory effects of TLR3 activation on CSD-induced neuroinflammation. Targeting TLR3 may provide a novel strategy for developing new treatments for CSD-related neurological disorders.


Spreading depolarization Migraine Stroke Cell death Immunotherapy Neuroprotection 



This work was supported by Shefa Neuroscience research center (Doctoral thesis 28198).


  1. 1.
    Leão AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7(6):359–390Google Scholar
  2. 2.
    Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81(3):1065–96PubMedGoogle Scholar
  3. 3.
    Gorji A (2001) Spreading depression: a review of the clinical relevance. Brain Res Brain Res Rev 38(1–2):33–60. doi: 10.1016/S0165-0173(01)00081-9 PubMedCrossRefGoogle Scholar
  4. 4.
    Dreier JP, Major S, Pannek HW, Woitzik J, Scheel M, Wiesenthal D, Martus P, Winkler MK, Hartings JA, Fabricius M, Speckmann EJ, Gorji A (2012) Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex. Brain 135(1):259–75. doi: 10.1093/brain/awr303 PubMedCrossRefGoogle Scholar
  5. 5.
    Markowitz S, Saito K, Moskowitz MA (1987) Neurogenically mediated leakage of plasma protein occurs from blood vessels in dura mater but not brain. J Neurosci 7(12):4129–4136PubMedGoogle Scholar
  6. 6.
    Goadsby PJ, Edvinsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28(2):183–187. doi: 10.1002/ana.410280213 PubMedCrossRefGoogle Scholar
  7. 7.
    Arnold G, Reuter U, Kinze S, Wolf T, Einhaupl KM (1998) Migraine with aura shows gadolinium enhancement which is reversed following prophylactic treatment. Cephalalgia 18:644–646. doi: 10.1111/j.1468-2982.1998.1809644.x PubMedCrossRefGoogle Scholar
  8. 8.
    Iizuka T, Sakai F, Suzuki K, Igarashi H, Suzuki N (2006) Implication of augmented vasogenic leakage in the mechanism of persistent aura in sporadic hemiplegic migraine. Cephalalgia 26(3):332–335. doi: 10.1111/j.1468-2982.2005.01025.x PubMedCrossRefGoogle Scholar
  9. 9.
    Silberstein SD (2006) Preventive treatment of migraine. Trends Pharmacol Sci 27(8):410–5. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  10. 10.
    Murray KN, Buggey HF, Denes A, Allan SM (2013) Systemic immune activation shapes stroke outcome. Mol Cell Neurosci 53:14–25. doi: 10.1016/j.mcn.2012.09.004 PubMedCrossRefGoogle Scholar
  11. 11.
    Levy D (2012) Endogenous mechanisms underlying the activation and sensitization of meningeal nociceptors: the role of immuno-vascular interactions and cortical spreading depression. Curr Pain Headache Rep 16(3):270–7. doi: 10.1007/s11916-012-0255-1 PubMedCrossRefGoogle Scholar
  12. 12.
    Kraig RP, Mitchell HM, Christie-Pope B, Kunkler PE, White DM, Tang YP, Langan G (2010) TNF-α and microglial hormetic involvement in neurological health & migraine. Dose Response 8(4):389–413. doi: 10.2203/dose-response.09-056.Kraig PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kunkler PE, Hulse RE, Kraig RP (2004) Multiplexed cytokine protein expression profiles from spreading depression in hippocampal organotypic cultures. J Cereb Blood Flow Metab 24(8):829–39. doi: 10.1097/01.WCB.0000126566.34753.30 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Frenkel D, Huang Z, Maron R, Koldzic DN, Hancock WW, Moskowitz MA, Weiner HL (2003) Nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. J Immunol 171(12):6549–55. doi: 10.4049/jimmunol.171.12.6549 PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang X, Burstein R, Levy D. Local action of the proinflammatory cytokines IL-1β and IL-6 on intracranial meningeal nociceptors. Cephalalgia 32 (1):66–72. doi: 10.1177/0333102411430848Google Scholar
  16. 16.
    Cheng YS, Xu F (2010) Anticancer function of polyinosinic-polycytidylic acid. Cancer Biol Ther 10(12):1219–1223. doi: 10.4161/cbt.10.12.13450 PubMedCrossRefGoogle Scholar
  17. 17.
    Matsumoto M, Seya T (2008) TLR3: Interferon induction by double-stranded RNA including poly (I:C). Adv Drug Deliv Rev 60:805–812. doi: 10.1186/1743-422X-9-114 PubMedCrossRefGoogle Scholar
  18. 18.
    Chang ZL (2010) Important aspects of Toll-like receptors, ligands and their signaling pathways. Inflamm Res 59(10):791–808. doi: 10.1007/s00011-010-0208-2 PubMedCrossRefGoogle Scholar
  19. 19.
    Chen XZ, Mao XH, Zhu KJ, Jin N, Ye J, Cen JP, Zhou Q, Cheng H (2010) Toll like receptor agonists augment HPV 11 E7-specific T cell responses by modulating monocyte-derived dendritic cells. Arch Dermatol Res 302(1):57–65. doi: 10.1007/s00403-009-0976-0 PubMedCrossRefGoogle Scholar
  20. 20.
    Sajadian A, Tabarraei A, Soleimanjahi H, Fotouhi F, Gorji A, Ghaemi A (2014) Comparing the effect of Toll-like receptor agonist adjuvants on the efficiency of a DNA vaccine. Arch Virol 159(8):1951–1960. doi: 10.1007/s00705-014-2024-4 PubMedCrossRefGoogle Scholar
  21. 21.
    Bsibsi M, Bajramovic JJ, Vogt MH, van Duijvenvoorden E, Baghat A, Persoon-Deen C, Tielen F, Verbeek R, Huitinga I, Ryffel B, Kros A, Gerritsen WH, Amor S, van Noort JM (2010) The microtubule regulator stathmin is an endogenous protein agonist for TLR3. J Immunol 184(12):6929–37. doi: 10.4049/jimmunol.0902419 PubMedCrossRefGoogle Scholar
  22. 22.
    Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, Flavell R, Strittmatter SM, Volpe J, Sidman R, Vartanian T (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27(47):13033–41. doi: 10.1523/JNEUROSCI. 4290-06.2007 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bosca L, Bodelon OG, Hortelano S, Casellas A, Bosch F (2000) Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta. Gene Ther 7(10):817–825PubMedCrossRefGoogle Scholar
  24. 24.
    Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort J (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53(7):688–95. doi: 10.1002/glia.20328 PubMedCrossRefGoogle Scholar
  25. 25.
    Pan LN, Zhu W, Li Y, Xu XL, Guo LJ, Lu Q, Wang J (2014) Astrocytic toll-like receptor 3 is associated with ischemic preconditioning- induced protection against brain ischemia in rodents. PLoS ONE 9(6):e99526. doi: 10.1371/journal.pone.0099526 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Rafiei A, Abedini M, Hosseini SH, Hosseini-Khah Z, Bazrafshan B, Tehrani M (2012) Toll like receptor-4 896A/G gene variation, a risk factor for migraine headaches. Iran J Immunol 9(3):159–67PubMedGoogle Scholar
  27. 27.
    Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates. Academic, San DiegoGoogle Scholar
  28. 28.
    Jafarian M, Rahimi S, Behnam F, Hosseini M, Haghir H, Sadeghzadeh B, Gorji A (2010) The effect of repetitive spreading depression on neuronal damage in juvenile rat brain. Neuroscience 169(1):388–94. doi: 10.1016/j.neuroscience.2010.04.062 PubMedCrossRefGoogle Scholar
  29. 29.
    Sadeghian H, Jafarian M, Karimzadeh F, Kafami L, Kazemi H, Coulon P, Ghabaee M, Gorji A (2012) Neuronal death by repetitive cortical spreading depression in juvenile rat brain. Exp Neurol 233(1):438–46. doi: 10.1016/j.expneurol.2011.11.017 PubMedCrossRefGoogle Scholar
  30. 30.
    Turturici G, Sconzo G, Geraci F (2011) Hsp70 and its molecular role in nervous system diseases. Biochem Res Int 2011:618127. doi: 10.1155/2011/618127 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Wernsmann B, Pape HC, Speckmann EJ, Gorji A (2006) Effect of cortical spreading depression on synaptic transmission of rat hippocampal tissues. Eur J Neurosci 23(5):1103–10. doi: 10.1111/j.1460-9568.2006.04643.x PubMedCrossRefGoogle Scholar
  32. 32.
    Martens-Mantai T, Speckmann EJ, Gorji A (2014) Propagation of cortical spreading depression into the hippocampus: the role of the entorhinal cortex. Synapse 68(12):574–584. doi: 10.1002/syn.21769 CrossRefGoogle Scholar
  33. 33.
    Jander S, Schroeter M, Peters O, Witte OW, Stoll G (2001) Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab 21(3):218–25. doi: 10.1097/00004647-200103000-00005 PubMedCrossRefGoogle Scholar
  34. 34.
    Thompson CS, Hakim AM (2005) Cortical spreading depression modifies components of the inflammatory cascade. Mol Neurobiol 32(1):51–7. doi: 10.1385/MN:32:1:051 PubMedCrossRefGoogle Scholar
  35. 35.
    Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Koçak E, Sen ZD, Dalkara T (2013) Spreading depression triggers headache by activating neuronal Panx1 channels. Science 339(6123):1092–5. doi: 10.1126/science.1231897 PubMedCrossRefGoogle Scholar
  36. 36.
    Chang RC, Hudson PM, Wilson BC, Liu B, Abel H, Hong JS (2000) High concentrations of extracellular potassium enhance bacterial endotoxin lipopolysaccharide-induced neurotoxicity in glia-neuron mixed cultures. Neuroscience 97(4):757–64. doi: 10.1016/S0306-4522(00)00059-2 PubMedCrossRefGoogle Scholar
  37. 37.
    Lauritzen M, Hansen AJ, Kronborg D, Wieloch T (1990) Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge. J Cereb Blood Flow Metab 10(1):115–22. doi: 10.1038/jcbfm.1990.14 PubMedCrossRefGoogle Scholar
  38. 38.
    Becker KJ (2010) Modulation of the postischemic immune response to improve stroke outcome. Stroke 41(10):S75–8. doi: 10.1161/STROKEAHA.110.592881 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Covelli V, Maffione AB, Munno I, Jirillo E (1990) Alterations of nonspecific immunity in patients with common migraine. J Clin Lab Anal 4(1):9–15PubMedCrossRefGoogle Scholar
  40. 40.
    Barbanti P, Bronzetti E, Ricci A, Cerbo R, Fabbrini G, Buzzi MG, Amenta F, Lenzi GL (1996) Increased density of dopamine D-5 receptor in peripheral blood lymphocytes of migraineurs: a marker for migraine? Neurosci Lett 207(2):73–6. doi: 10.1016/0304-3940(96)12491-5 PubMedCrossRefGoogle Scholar
  41. 41.
    Kuritzky A, Bennet E, Hering R, Ebstein R (1993) Reduced sensitivity of lymphocyte beta-adrenergic receptors in migraine. Headache 33(4):198–200. doi: 10.1111/j.1526-4610.1993.hed33040198.x PubMedCrossRefGoogle Scholar
  42. 42.
    Leone M, Sacerdote P, D’Amico D, Panerai AE, Bussone G (1992) Beta-endorphin concentrations in the peripheral blood mononuclear cells of migraine and tension-type headache patients. Cephalalgia 12:154–7. doi: 10.1046/j.1468-2982.1992.1203155.x PubMedCrossRefGoogle Scholar
  43. 43.
    Covelli V, Munno I, Pellegrino NM, Attamura M, Decandia P, Marcuccio C, Di Venere A, Jirillo E (1991) Are TNF-alpha and IL-1 beta relevant in the pathogenesis of migraine without aura? Acta Neurol (Napoli) 13(2):205–11Google Scholar
  44. 44.
    Martelletti P, Stirparo G, Rinaldi C, Frati L, Giacovazzo M (1993) Disruption of the immunopeptidergic network in dietary migraine. Headache 33(10):524–7. doi: 10.1111/j.1526-4610.1993.hed3310524.x PubMedCrossRefGoogle Scholar
  45. 45.
    Kallen B, Nilsson O, Thelin C (1977) Effect of encephalitogenic protein on migration in agarose of leukocytes from patients with multiple sclerosis. A longitudinal study of patients with relapsing multiple sclerosis or with cerebral infarction. Acta Neurol Scand 55(1):47–56. doi: 10.1111/j.1600-0404.1977.tb05625.x CrossRefGoogle Scholar
  46. 46.
    Wang WZ, Olsson T, Kostulas V, Hojeberg B, Ekre HP, Link H (1992) Myelin antigen reactive t cells in cerebrovascular diseases. Clin Exp Immunol 88(1):157–162. doi: 10.1111/j.1365-2249.1992.tb03056.x PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Yong VW, Rivest S (2009) Taking advantage of the systemic immune system to cure brain diseases. Neuron 64(1):55–60. doi: 10.1016/j.neuron.2009.09.035 PubMedCrossRefGoogle Scholar
  48. 48.
    Kreutzberg GW (1995) Microglia, the first line of defence in brain pathologies. Arzneimittelforschung 45(3A):357–60PubMedGoogle Scholar
  49. 49.
    Schwartz M, Moalem G, Leibowitz-Amit R, Cohen IR (1999) Innate and adaptive immune responses can be beneficial for CNS repair. Trends Neurosci 22(7):295–299. doi: 10.1016/S0166-2236(99)01405-8 PubMedCrossRefGoogle Scholar
  50. 50.
    Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64(1):110–122. doi: 10.1016/j.neuron.2009.08.039 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Richter F, Lütz W, Eitner A, Leuchtweis J, Lehmenkühler A, Schaible HG (2014) Tumor necrosis factor reduces the amplitude of rat cortical spreading depression in vivo. Ann Neurol 76(1):43–53. doi: 10.1002/ana.24176 PubMedCrossRefGoogle Scholar
  52. 52.
    Calabrese EJ, Baldwin LA (2003) Hormesis: the dose–response revolution. Annu Rev Pharmacol Toxicol 43:175–197. doi: 10.1146/annurev.pharmtox.43.100901.140223 PubMedCrossRefGoogle Scholar
  53. 53.
    Pusic KM, Pusic AD, Kemme J, Kraig RP (2014) Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment. Glia 62:1176–94. doi: 10.1002/glia.22672 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604. doi: 10.1016/j.immuni.2010.05.007 PubMedCrossRefGoogle Scholar
  55. 55.
    Chan A, Magnus T, Gold R (2001) Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system. Glia 33(1):87–95. doi: 10.1002/1098-1136(20010101)33:1<87:AID-GLIA1008>3.0.CO;2-S PubMedCrossRefGoogle Scholar
  56. 56.
    Szczepanik AM, Funes S, Petko W, Ringheim GE (2001) IL-4, IL-10 and IL-13 modulate A beta (1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 113(1):49–62. doi: 10.1016/S0165-5728(00)00404-5 PubMedCrossRefGoogle Scholar
  57. 57.
    Kobayashi S, Harris VA, Welsh FA (1995) Spreading depression induces tolerance of cortical neurons to ischemia in rat brain. J Cereb Blood Flow Metab 15(5):721–727. doi: 10.1038/jcbfm.1995.93 PubMedCrossRefGoogle Scholar
  58. 58.
    Hermann DM, Mies G, Hossmann KA (1999) Expression of c-fos, junB, c-jun, MKP-1 and hsp72 following traumatic neocortical lesions in rats–relation to spreading depression. Neuroscience 88(2):599–608. doi: 10.1016/S0306-4522(98)00249-8 PubMedCrossRefGoogle Scholar
  59. 59.
    Rangel YM, Karikó K, Harris VA, Duvall ME, Welsh FA (2001) Dose-dependent induction of mRNAs encoding brain-derived neurotrophic factor and heat-shock protein-72 after cortical spreading depression in the rat. Brain Res Mol Brain Res 88(1–2):103–12. doi: 10.1016/S0169-328X(01)00037-7 PubMedCrossRefGoogle Scholar
  60. 60.
    Dietrich WD, Truettner J, Prado R, Stagliano NE, Zhao W, Busto R, Ginsberg MD, Watson BD (2000) Thromboembolic events lead to cortical spreading depression and expression of c-fos, brain-derived neurotrophic factor, glial fibrillary acidic protein, and heat shock protein 70 mRNA in rats. J Cereb Blood Flow Metab 20(1):103–11. doi: 10.1097/00004647-200001000-00014 PubMedCrossRefGoogle Scholar
  61. 61.
    Aoki M, Abe K, Kawagoe J, Nakamura S, Kogure K (1993) Acceleration of HSP70 and HSC70 heat shock gene expression following transient ischemia in the preconditioned gerbil hippocampus. J Cereb Blood Flow Metab 13(5):781–788. doi: 10.1038/jcbfm.1993.99 PubMedCrossRefGoogle Scholar
  62. 62.
    de Freitas MS, Spohr TC, Benedito AB, Caetano MS, Margulis B, Lopes UG, Moura-Neto V (2002) Neurite outgrowth is impaired on HSP70-positive astrocytes through a mechanism that requires NF-kappaB activation. Brain Res 958(2):359–70. doi: 10.1016/S0006-8993(02)03682-X PubMedCrossRefGoogle Scholar
  63. 63.
    Ooigawa H, Nawashiro H, Fukui S, Otani N, Osumi A, Toyooka T, Shima K (2006) The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate. Acta Neuropathol 112(4):471–81. doi: 10.1007/s00401-006-0108-2 PubMedCrossRefGoogle Scholar
  64. 64.
    Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 2(7):788–94. doi: 10.1038/nm0796-788 PubMedCrossRefGoogle Scholar
  65. 65.
    Mizuno T, Zhang G, Takeuchi H, Kawanokuchi J, Wang J, Sonobe Y, Jin S, Takada N, Komatsu Y, Suzumura A (2008) Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J 22(6):1797–806. doi: 10.1096/fj.07-099499 PubMedCrossRefGoogle Scholar
  66. 66.
    Tsuchiya D, Hong S, Matsumori Y, Kayama T, Swanson RA, Dillman WH, Liu J, Panter SS, Weinstein PR (2003) Overexpression of rat heat shock protein 70 reduces neuronal injury after transient focal ischemia, transient global ischemia, or kainic acid-induced seizures. Neurosurgery 53(5):1179–87. doi: 10.1227/01.NEU.0000090341.38659.CF PubMedCrossRefGoogle Scholar
  67. 67.
    Berger M, Speckmann EJ, Pape HC, Gorji A (2008) Spreading depression enhances human neocortical excitability in vitro. Cephalalgia 28(5):558–62. doi: 10.1111/j.1468-2982.2008.01556.x PubMedCrossRefGoogle Scholar
  68. 68.
    Ghadiri MK, Kozian M, Ghaffarian N, Stummer W, Kazemi H, Speckmann EJ, Gorji A (2012) Sequential changes in neuronal activity in single neocortical neurons after spreading depression. Cephalalgia 32(2):116–24. doi: 10.1177/0333102411431308 PubMedCrossRefGoogle Scholar
  69. 69.
    Eickhoff M, Kovac S, Shahabi P, Ghadiri MK, Dreier JP, Stummer W, Speckmann EJ, Pape HC, Gorji A (2014) Spreading depression triggers ictaform activity in partially disinhibited neuronal tissues. Exp Neurol 253:1–15. doi: 10.1016/j.expneurol.2013.12.008 PubMedCrossRefGoogle Scholar
  70. 70.
    Marty S, Wehrlé R, Sotelo C (2000) Neuronal activity and brain-derived neurotrophic factor regulate the density of inhibitory synapses in organotypic slice cultures of postnatal hippocampus. J Neurosci 20(21):8087–95PubMedGoogle Scholar
  71. 71.
    Knopp A, Frahm C, Fidzinski P, Witte OW, Behr J (2008) Loss of GABAergic neurons in the subiculum and its functional implications in temporal lobe epilepsy. Brain 131(Pt 6):1516–27. doi: 10.1093/brain/awn095 PubMedCrossRefGoogle Scholar
  72. 72.
    Pribiag H, Stellwagen D (2013) TNF-alpha downregulates inhibitory neurotransmission through protein phosphatase 1-dependent trafficking of GABAA receptors. J Neurosci 33(40):15879–15893. doi: 10.1523/JNEUROSCI. 0530-13.2013 PubMedCrossRefGoogle Scholar
  73. 73.
    Paul AM, Branton WG, Walsh JG, Polyak MJ, Lu JQ, Baker GB, Power C (2014) GABA transport and neuroinflammation are coupled in multiple sclerosis: regulation of the GABA transporter-2 by ganaxolone. Neuroscience 273:24–38. doi: 10.1016/j.neuroscience.2014.04.037 PubMedCrossRefGoogle Scholar
  74. 74.
    Wei M, Li L, Meng R, Fan Y, Liu Y, Tao L, Liu X, Wu C (2010) Suppressive effect of diazepam on IFN-gamma production by human T cells. Int Immunopharmacol 10(3):267–71. doi: 10.1016/j.intimp.2009.11.009 PubMedCrossRefGoogle Scholar
  75. 75.
    Van Harreveld A, Kooiman M (1965) Amino acid release from the cerebral cortex during spreading depression and asphyxiation. J Neurochem 12:431–439CrossRefGoogle Scholar
  76. 76.
    Muir JK, Lobner D, Monyer H, Choi DW (1996) GABAA receptor activation attenuates excitotoxicity but exacerbates oxygen-glucose deprivation-induced neuronal injury in vitro. J Cereb Blood Flow Metab 16(6):1211–8. doi: 10.1097/00004647-199611000-00015 PubMedCrossRefGoogle Scholar
  77. 77.
    de Almeida OM, Gardino PF, Loureiro dos Santos NE, Yamasaki EN, de Mello MC, Hokoç JN, de Mello FG (2002) Opposite roles of GABA and excitatory amino acids on the control of GAD expression in cultured retina cells. Brain Res 925(1):89–99. doi: 10.1016/S0006-8993(01)03265-6 PubMedCrossRefGoogle Scholar
  78. 78.
    Rimvall K, Sheikh SN, Martin DL (1993) Effects of increased gamma-aminobutyric acid levels on GAD67 protein and mRNA levels in rat cerebral cortex. J Neurochem 60(2):714–20. doi: 10.1111/j.1471-4159.1993.tb03206.x PubMedCrossRefGoogle Scholar
  79. 79.
    Marsh B, Stevens SL, Packard AE, Gopalan B, Hunter B, Leung PY, Harrington CA, Stenzel-Poore MP (2009) Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci 29(31):9839–49. doi: 10.1523/JNEUROSCI. 2496-09.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Marsh BJ, Stenzel-Poore MP (2008) Toll-like receptors: novel pharmacological targets for the treatment of neurological diseases. Curr Opin Pharmacol 8(1):8–13. doi: 10.1016/j.coph.2007.09.009 PubMedCrossRefGoogle Scholar
  81. 81.
    Gesuete R, Kohama SG, Stenzel-Poore MP (2014) Toll-like receptors and ischemic brain injury. J Neuropathol Exp Neurol 73(5):378–86. doi: 10.1097/NEN.0000000000000068 PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Bahjat FR, Williams-Karnesky RL, Kohama SG, West GA, Doyle KP, Spector MD, Hobbs TR, Stenzel-Poore MP (2011) Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. J Cereb Blood Flow Metab 31(5):1229–42. doi: 10.1038/jcbfm.2011.6 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Hua F, Ma J, Ha T, Kelley JL, Kao RL, Schweitzer JB, Kalbfleisch JH, Williams DL, Li C (2009) Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Res 1262:100–8. doi: 10.1016/j.brainres.2009.01.018 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ (2007) Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun 353(2):509–14. doi: 10.1016/j.bbrc.2006.12.057 PubMedCrossRefGoogle Scholar
  85. 85.
    Pan LN, Zhu W, Li C, Xu XL, Guo LJ, Lu Q (2012) Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol Sin 33(10):1246–53. doi: 10.1038/aps.2012.122 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Zhang X, Ha T, Lu C, Lam F, Liu L, Schweitzer J, Kalbfleisch J, Kao RL, Williams DL, Li C (2014) Poly (I:C) therapy decreases cerebral ischaemia/reperfusion injury via TLR3-mediated prevention of Fas/FADD interaction. J Cell Mol Med. doi: 10.1111/jcmm.12456 [Epub ahead of print]Google Scholar
  87. 87.
    Liu T, Berta T, Xu ZZ, Park CK, Zhang L, Lü N, Liu Q, Liu Y, Gao YJ, Liu YC, Ma Q, Dong X, Ji RR (2012) TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J Clin Invest 122(6):2195–207. doi: 10.1172/JCI45414 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Amir Ghaemi
    • 1
    • 2
  • Azadeh Sajadian
    • 1
  • Babak Khodaie
    • 1
  • Ahmad Ali Lotfinia
    • 1
  • Mahmoud Lotfinia
    • 1
  • Afsaneh Aghabarari
    • 1
  • Maryam Khaleghi Ghadiri
    • 3
  • Sven Meuth
    • 4
  • Ali Gorji
    • 1
    • 5
    • 6
    Email author
  1. 1.Shefa Neuroscience Research CenterTehranIran
  2. 2.Department of MicrobiologyGolestan University of Medical SciencesGorganIran
  3. 3.Klinik und Poliklinik für NeurochirurgieWestfälischeWilhelms-Universität MünsterMünsterGermany
  4. 4.Department of NeurologyWestfälischeWilhelms-Universität MünsterMünsterGermany
  5. 5.Institut für Physiologie IWestfälischeWilhelms-Universität MünsterMünsterGermany
  6. 6.Epilepsy Research CenterUniversität MünsterMünsterGermany

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