Inflammation is established as a contributor to cerebrovascular disease. Risk factors for stroke include many conditions associated with chronic or acute inflammation, and inflammatory changes in the brain after cerebrovascular events contribute to outcome in experimental studies, with growing evidence from clinical research. The brain is extremely susceptible to inflammatory challenge, but resident glia, endothelial cells and neurones can all mount a pronounced inflammatory response to infection or injury. Recent discoveries highlight the importance of peripherally-derived immune cells and inflammatory molecules in various central nervous system disorders, including stroke. The inflammatory cytokine, interleukin-1 (IL-1), plays a pivotal role in both local and systemic inflammation, and is a key driver of peripheral and central immune responses to infection or injury. Inhibition of IL-1 has beneficial effects in a variety of experimental paradigms of acute brain injury and is a promising clinical target in stroke. We propose that blockade of IL-1 could be therapeutically useful in several diseases which are risk factors for stroke, and there is already considerable pre-clinical and clinical evidence that inhibition of IL-1 by IL-1 receptor antagonist may be valuable in the management of acute stroke.

Keywords:
Interleukin-1, IL-1Ra
1.
Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752–2758.
2.
Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009;40:2244–2250.
3.
Banwell V, Sena ES, Macleod MR: Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. J Stroke Cerebrovasc Dis 2009;18:269–276.
4.
Parry-Jones A, Boutin H, Denes A, McColl B, Hopkins S, Allan S, Tyrrell P: Interleukin-1 receptor antagonist in animal models of stroke: a fair summing up? J Stroke Cerebrovasc Dis 2010;19:512–513.
5.
Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL: Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nature medicine 2007;13:851–856.
6.
Giulian D, Lachman LB: Interleukin-1 stimulation of astroglial proliferation after brain injury. Science 1985;228:497–499.
7.
Woodroofe MN, Sarna GS, Wadhwa M, Hayes GM, Loughlin AJ, Tinker A, Cuzner ML: Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production. J Neuroimmunol 1991;33:227–236.
8.
Quagliarello VJ, Wispelwey B, Long WJ Jr, Scheld WM: Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat: characterization and comparison with tumor necrosis factor. J Clin Invest 1991;87:1360–1366.
9.
Giulian D, Woodward J, Young DG, Krebs JF, Lachman LB: Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci 1988;8:2485–2490.
10.
Relton JK, Rothwell NJ: Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat. Brain Res Bull 1992;29:243–246.
11.
Touzani O, Boutin H, LeFeuvre R, Parker L, Miller A, Luheshi G, Rothwell N: Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type i receptor. J Neurosci 2002;22:38–43.
12.
Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ: Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 2001;21:5528–5534.
13.
Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K: Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke 1995;26:676–680.
14.
Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ: A selective, non-peptide caspase-1 inhibitor, vrt-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology 2007;53:638–642.
15.
Loddick SA, MacKenzie A, Rothwell NJ: An ICE inhibitor, z-vad-dcb attenuates ischaemic brain damage in the rat. Neuroreport 1996;7:1465–1468.
16.
Li H, Colbourne F, Sun P, Zhao Z, Buchan AM, Iadecola C: Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 2000;31:176–182.
17.
Wu B, Ma Q, Khatibi N, Chen W, Sozen T, Cheng O, Tang J: Ac-yvad-cmk decreases blood-brain barrier degradation by inhibiting caspase-1 activation of interleukin-1beta in intracerebral hemorrhage mouse model. Translational Stroke Res 2010;1:57–64.
18.
Suzuki H, Sozen T, Hasegawa Y, Chen W, Zhang JH: Caspase-1 inhibitor prevents neurogenic pulmonary edema after subarachnoid hemorrhage in mice. Stroke 2009;40:3872–3875.
19.
de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW: A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci 2008;28:3404–3414.
20.
de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW: Therapeutic neutralization of the nlrp1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 2009;29:1251–1261.
21.
Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD: Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 2009;29:534–544.
22.
Worrall BB, Azhar S, Nyquist PA, Ackerman RH, Hamm TL, DeGraba TJ: Interleukin-1 receptor antagonist gene polymorphisms in carotid atherosclerosis. Stroke 2003;34:790–793.
23.
Um JY, Moon KS, Lee KM, Yun JM, Cho KH, Moon BS, Kim HM: Association of interleukin-1 alpha gene polymorphism with cerebral infarction. Brain Res 2003;115:50–54.
24.
Dziedzic T, Slowik A, Pera J, Szczudlik A: Interleukin 1 beta polymorphism (–511) and risk of stroke due to small vessel disease. Cerebrovasc Dis 2005;20:299–303.
25.
Kim H, Hysi PG, Pawlikowska L, Poon A, Burchard EG, Zaroff JG, Sidney S, Ko NU, Achrol AS, Lawton MT, McCulloch CE, Kwok PY, Young WL: Common variants in interleukin-1-beta gene are associated with intracranial hemorrhage and susceptibility to brain arteriovenous malformation. Cerebrovasc Dis 2009;27:176–182.
26.
Seripa D, Dobrina A, Margaglione M, Matera MG, Gravina C, Vecile E, Fazio VM: Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke. Cerebrovasc Dis 2003;15:276–281.
27.
Rezaii AA, Hoseinipanah SM, Hajilooi M, Rafiei AR, Shikh N, Haidari M: Interleukin-1 receptor antagonist gene polymorphism and susceptibility to ischemic stroke. Immunol Invest 2009;38:220–230.
28.
Pinteaux E, Trotter P, Simi A: Cell-specific and concentration-dependent actions of interleukin-1 in acute brain inflammation. Cytokine 2009;45:1–7.
29.
Pinteaux E, Parker LC, Rothwell NJ, Luheshi GN: Expression of interleukin-1 receptors and their role in interleukin-1 actions in murine microglial cells. J Neurochem 2002;83:754–763.
30.
Greenfeder SA, Nunes P, Kwee L, Labow M, Chizzonite RA, Ju G: Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. J Biol Chem 1995;270:13757–13765.
31.
Greenfeder SA, Varnell T, Powers G, Lombard-Gillooly K, Shuster D, McIntyre KW, Ryan DE, Levin W, Madison V, Ju G: Insertion of a structural domain of interleukin (IL)-1 beta confers agonist activity to the IL-1 receptor antagonist. Implications for IL-1 bioactivity. J Biol Chem 1995;270:22460–22466.
32.
Huang J, Gao X, Li S, Cao Z: Recruitment of Irak to the interleukin 1 receptor complex requires interleukin 1 receptor accessory protein. Proc Natl Acad Sci USA 1997;94:12829–12832.
33.
Volpe F, Clatworthy J, Kaptein A, Maschera B, Griffin AM, Ray K: The IL1 receptor accessory protein is responsible for the recruitment of the interleukin-1 receptor associated kinase to the IL1/IL1 receptor i complex. FEBS Lett 1997;419:41–44.
34.
Gabellec MM, Jafarian-Tehrani M, Griffais R, Haour F: Interleukin-1 receptor accessory protein transcripts in the brain and spleen: kinetics after peripheral administration of bacterial lipopolysaccharide in mice. Neuroimmunomodulation 1996;3:304–309.
35.
Smith DE, Lipsky BP, Russell C, Ketchem RR, Kirchner J, Hensley K, Huang Y, Friedman WJ, Boissonneault V, Plante MM, Rivest S, Sims JE: A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1. Immunity 2009;30:817–831.
36.
Davis CN, Tabarean I, Gaidarova S, Behrens MM, Bartfai T: IL-1beta induces a myd88-dependent and ceramide-mediated activation of src in anterior hypothalamic neurons. J Neurochem 2006;98:1379–1389.
37.
Sanchez-Alavez M, Tabarean IV, Behrens MM, Bartfai T: Ceramide mediates the rapid phase of febrile response to IL-1beta. Proc Natl Acad Sci USA 2006;103:2904–2908.
38.
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M: Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the src family of kinases. J Neurosci 2003;23:8692–8700.
39.
Desson SE, Ferguson AV: Interleukin 1beta modulates rat subfornical organ neurons as a result of activation of a non-selective cationic conductance. J Physiol 2003;550:113–122.
40.
Sama MA, Mathis DM, Furman JL, Abdul HM, Artiushin IA, Kraner SD, Norris CM: Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/nfat activity. J Biol Chem 2008;283:21953–21964.
41.
Bolton SJ, Anthony DC, Perry VH: Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience 1998;86:1245–1257.
42.
Fogal B, Hewett SJ: Interleukin-1beta: a bridge between inflammation and excitotoxicity? J Neurochem 2008;106:1–23.
43.
Parker LC, Luheshi GN, Rothwell NJ, Pinteaux E: IL-1 beta signalling in glial cells in wildtype and IL-1ri deficient mice. Br J Pharmacol 2002;136:312–320.
44.
Herx LM, Yong VW: Interleukin-1 beta is required for the early evolution of reactive astrogliosis following CNS lesion. J Neuropathol Exp Neurol 2001;60:961–971.
45.
Thornton P, Pinteaux E, Allan SM, Rothwell NJ: Matrix metalloproteinase-9 and urokinase plasminogen activator mediate interleukin-1-induced neurotoxicity. Mol Cell Neurosci 2008;37:135–142.
46.
Thornton P, McColl BW, Cooper L, Rothwell NJ, Allan SM: Interleukin-1 drives cerebrovascular inflammation via map kinase-independent pathways. Curr Neurovasc Res 2011;7:330–340.
47.
Ching S, Zhang H, Belevych N, He L, Lai W, Pu XA, Jaeger LB, Chen Q, Quan N: Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration. J Neurosci 2007;27:10476–10486.
48.
Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E: Differential effects of interleukin-1 alpha and beta on interleukin-6 and chemokine synthesis in neurones. Mol Cell Neurosci 2008;38:259–265.
49.
Dinarello CA: Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011;117:3720–3732.
50.
Dinarello CA: Blocking interleukin-1beta in acute and chronic autoinflammatory diseases. J Intern Med 2011;269:16–28.
51.
Donath MY, Shoelson SE: Type 2 diabetes as an inflammatory disease. Nat Rev 2011;11:98–107.
52.
Dinarello CA: Blocking IL-1 in systemic inflammation. J Exp Med 2005;201:1355–1359.
53.
Rothwell NJ: CNS regulation of thermogenesis. Crit Rev Neurobiol 1994;8:1–10.
54.
Takahashi H, Nishimura M, Sakamoto M, Ikegaki I, Nakanishi T, Yoshimura M: Effects of interleukin-1 beta on blood pressure, sympathetic nerve activity, and pituitary endocrine functions in anesthetized rats. Am J Hypertens 1992;5:224–229.
55.
Niijima A, Hori T, Aou S, Oomura Y: The effects of interleukin-1 beta on the activity of adrenal, splenic and renal sympathetic nerves in the rat. J Autonom Nerv Syst 1991;36:183–192.
56.
Kannan H, Tanaka Y, Kunitake T, Ueta Y, Hayashida Y, Yamashita H: Activation of sympathetic outflow by recombinant human interleukin-1 beta in conscious rats. Am J Physiol 1996;270:R479–R485.
57.
McColl BW, Allan SM, Rothwell NJ: Systemic infection, inflammation and acute ischemic stroke. Neuroscience 2009;158:1049–1061.
58.
Denes A, Thornton P, Rothwell NJ, Allan SM: Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immunity 2010;24:708–723.
59.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD: The nlrp3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011;17:179–188.
60.
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E: Nlrp3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357–1361.
61.
Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP: Fatty acid-induced nlrp3-asc inflammasome activation interferes with insulin signaling. Nat Immunol 2011;12:408–415.
62.
Chamberlain J, Francis S, Brookes Z, Shaw G, Graham D, Alp NJ, Dower S, Crossman DC: Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PloS One 2009;4:e5073.
63.
Drake C, Boutin H, Jones MS, et al: Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav Immunity 2011;25:1113–1122.
64.
McColl BW, Rothwell NJ, Allan SM: Systemic inflammatory stimulus potentiates the acute phase and cxc chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J Neurosci 2007;27:4403–4412.
65.
McColl BW, Rothwell NJ, Allan SM: Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 2008;28:9451–9462.
66.
Konsman JP, Drukarch B, Van Dam AM: (Peri)vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond) 2007;112:1–25.
67.
Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ: Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 2010;115:3632–3639.
68.
Zeller JA, Lenz A, Eschenfelder CC, Zunker P, Deuschl G: Platelet-leukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler Thromb Vasc Biol 2005;25:1519–1523.
69.
van der Poll T, Levi M, Hack CE, et al: Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994;179:1253–1259.
70.
van der Poll T, Levi M, Buller HR, van Deventer SJ, de Boer JP, Hack CE, ten Cate JW: Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991;174:729–732.
71.
Dejana E, Breviario F, Erroi A, et al: Modulation of endothelial cell functions by different molecular species of interleukin 1. Blood 1987;69:695–699.
72.
Shebuski RJ, Kilgore KS: Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002;300:729–735.
73.
Jansen PM, Boermeester MA, Fischer E, de Jong IW, van der Poll T, Moldawer LL, Hack CE, Lowry SF: Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia. Blood 1995;86:1027–1034.
74.
Denes A, Humphreys N, Lane TE, Grencis R, Rothwell N: Chronic systemic infection exacerbates ischemic brain damage via a ccl5 (regulated on activation, normal T-cell expressed and secreted)-mediated proinflammatory response in mice. J Neurosci 2010;30:10086–10095.
75.
Lanska DJ, Hoffmann RG: Seasonal variation in stroke mortality rates. Neurology 1999;52:984–990.
76.
Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M: Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med 2003;348:1322–1332.
77.
Muhammad S, Haasbach E, Kotchourko M, Strigli A, Krenz A, Ridder DA, Vogel AB, Marti HH, Al-Abed Y, Planz O, Schwaninger M: Influenza virus infection aggravates stroke outcome. Stroke 2011;42:783–791.
78.
Rupp J, Kothe H, Mueller A, Maass M, Dalhoff K: Imbalanced secretion of IL-1beta and IL-1ra in Chlamydia pneumoniae-infected mononuclear cells from COPD patients. Eur Respir J 2003;22:274–279.
79.
Endeman H, Meijvis SC, Rijkers GT, van Velzen-Blad H, van Moorsel CH, Grutters JC, Biesma DH: Systemic cytokine response in patients with community-acquired pneumonia. Eur Respir J 2011;37:1431–1438.
80.
Calbo E, Alsina M, Rodriguez-Carballeira M, Lite J, Garau J: The impact of time on the systemic inflammatory response in pneumococcal pneumonia. Eur Respir J 2010;35:614–618.
81.
Kafka D, Ling E, Feldman G, Benharroch D, Voronov E, Givon-Lavi N, Iwakura Y, Dagan R, Apte RN, Mizrachi-Nebenzahl Y: Contribution of IL-1 to resistance to Streptococcus pneumoniae infection. Int Immunol 2008;20:1139–1146.
82.
Herold S, Tabar TS, Janssen H, Hoegner K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmueller M, Lohmeyer J: Exudate macrophages attenuate lung injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Resp Crit Care Med 2011;183:1380–1390.
83.
Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, Schnyder B, Akira S, Quesniaux VF, Lagente V, Ryffel B, Couillin I: IL-1r1/myd88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest 2007;117:3786–3799.
84.
Carrol ED, Payton A, Payne D, Miyajima F, Chaponda M, Mankhambo LA, Banda DL, Molyneux EM, Cox H, Jacobson G, Carr DF, Molyneux ME, Stewart JP, Quinn JP, Hart CA, Ollier WE: The IL1rn promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by gata-1. J Immunol 2011;186:2329–2335.
85.
Bermejo-Martin JF, Martin-Loeches I, Rello J, et al: Host adaptive immunity deficiency in severe pandemic influenza. Crit Care 2010;14:R167.
86.
Tanzi P, Cain K, Kalil A, Zierath D, Savos A, Gee JM, Shibata D, Hadwin J, Carter K, Becker K: Post-stroke infection: a role for IL-1ra? Neurocritic Care;14:244–252.
87.
Curti BD, Urba WJ, Longo DL, Janik JE, Sharfman WH, Miller LL, Cizza G, Shimizu M, Oppenheim JJ, Alvord WG, Smith JW 2nd: Endocrine effects of IL-1 alpha and beta administered in a phase i trial to patients with advanced cancer. J Immunother Emphasis Tumor Immunol 1996;19:142–148.
88.
Sundar SK, Cierpial MA, Kilts C, Ritchie JC, Weiss JM: Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor. J Neurosci 1990;10:3701–3706.
89.
Sullivan GM, Canfield SM, Lederman S, Xiao E, Ferin M, Wardlaw SL: Intracerebroventricular injection of interleukin-1 suppresses peripheral lymphocyte function in the primate. Neuroimmunomodulation 1997;4:12–18.
90.
Gelin JL, Moldawer LL, Iresjo BM, Lundholm KG: The role of the adrenals in the acute phase response to interleukin-1 and tumor necrosis factor-alpha. J Surg Res 1993;54:70–78.
91.
Medvedev AE, Lentschat A, Wahl LM, Golenbock DT, Vogel SN: Dysregulation of LPS-induced toll-like receptor 4-myd88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol 2002;169:5209–5216.
92.
Beishuizen A, Thijs LG: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotox Res 2003;9:3–24.
93.
Smith CJ EH, Hoadley ME, Hopkins SJ, Rothwell NJ TP, Udeh CT, Vail A: Interleukin-1 receptor antagonist reverses stroke-associated peripheral immunodepression. Int J Stroke 2010;5(suppl 3):3–13.
94.
Kopf M, Bachmann MF, Marsland BJ: Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov 2010;9:703–718.
95.
Diem R, Hobom M, Grotsch P, Kramer B, Bahr M: Interleukin-1 beta protects neurons via the interleukin-1 (IL-1) receptor-mediated akt pathway and by IL-1 receptor-independent decrease of transmembrane currents in vivo. Mol Cell Neurosci 2003;22:487–500.
96.
Li Q, Zhang H, Chen Q, Quan N: Existence of seven human IL-1r1 promoters. J Inflamm Res 2010;17–24.
97.
Quiniou C, Sapieha P, Lahaie I, Hou X, Brault S, Beauchamp M, Leduc M, Rihakova L, Joyal JS, Nadeau S, Heveker N, Lubell W, Sennlaub F, Gobeil F Jr, Miller G, Pshezhetsky AV, Chemtob S: Development of a novel noncompetitive antagonist of IL-1 receptor. J Immunol 2008;180:6977–6987.
98.
Boutard N, Turcotte S, Beauregard K, Quiniou C, Chemtob S, Lubell WD: Examination of the active secondary structure of the peptide 101.10, an allosteric modulator of the interleukin-1 receptor, by positional scanning using beta-amino gamma-lactams. J Pept Sci 2011;17:288–296.
99.
Wang D, Zhang S, Li L, Liu X, Mei K, Wang X: Structural insights into the assembly and activation of IL-1beta with its receptors. Nature Immunol 2010;11:905–911.
100.
Macleod MR, O’Collins T, Howells DW, Donnan GA: Pooling of animal experimental data reveals influence of study design and publication bias. Stroke 2004;35:1203–1208.
101.
Allan SM, Tyrrell PJ, Rothwell NJ: Interleukin-1 and neuronal injury. Nat Rev 2005;5:629–640.
102.
Rothwell N: Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003;17:152–157.
103.
Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ: A randomised phase ii study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005;76:1366–1372.
104.
Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, Kremer J, Bear MB, Rich WJ, McCabe D: Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614–624.
105.
Clark SR, McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R, Tyrrell PJ, Hopkins SJ, Rothwell NJ: Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. J Cereb Blood Flow Metab 2008;28:387–394.
106.
Gueorguieva I, Clark SR, McMahon CJ, Scarth S, Rothwell NJ, Tyrrell PJ, Hopkins SJ, Rowland M: Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage. Br J Clin Pharmacol 2008;65:317–325.
107.
Greenhalgh AD, Galea J, Denes A, Tyrrell PJ, Rothwell NJ: Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection. Br J Pharmacol 2010;160:153–159.
108.
Galea J, Ogungbenro K, Hulme S, Greenhalgh A, Aarons L, Scarth S, Hutchinson P, Grainger S, King A, Hopkins SJ, Rothwell N, Tyrrell P: Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study. J Cereb Blood Flow Metab 2011;31:439–447.
109.
Ischenko AM, Nikolaev BP, Kotova TV, Vorobeychikov EV, Konusova VG, Yakovleva LY: IL-1 receptor antagonist as an aerosol in inflammation. J Aerosol Med 2007;20:445–459.
110.
Pradillo HB, Drake C, Denes A, McColl BW, Rothwell NJ, Allan SM: Effect of IL-1 receptor antagonist (IL1-Ra) administered subcutaneously after experimental stroke (reperfusion time) in rats with different stroke risk factors. BRAIN 2011. Barcelona, 2011.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.