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Therapeutics targeting the inflammasome after central nervous system injury

  • Juan Pablo de Rivero Vaccari
    Correspondence
    Reprint requests: Juan Pablo de Rivero Vaccari, Department of Neurological Surgery, Lois Pope LIFE Center, 1095 NW 14th Terrace, 3-25JJ, Miami, FL 33136-1060
    Affiliations
    Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fla
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  • W. Dalton Dietrich
    Affiliations
    Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fla
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  • Robert W. Keane
    Affiliations
    Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Fla

    Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Fla
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      Innate immunity is part of the early response of the body to deal with tissue damage and infections. Because of the early nature of the innate immune inflammatory response, this inflammatory reaction represents an attractive option as a therapeutic target. The inflammasome is a component of the innate immune response involved in the activation of caspase 1 and the processing of pro–interleukin 1β. In this article, we discuss the therapeutic potential of the inflammasome after central nervous system (CNS) injury and stroke, as well as the basic knowledge we have gained so far regarding inflammasome activation in the CNS. In addition, we discuss some of the therapies available or under investigation for the treatment of brain injury, spinal cord injury, and stroke.

      Abbreviations:

      AIM (Absent in melanoma), ASC (Apoptosis-associated speck-like protein containing a caspase activating recruitment domain), ATP (Adenosine triphosphate), ASC (Apoptosis-associated speck-like protein containing a caspase activating recruitment domain), BACE1 (β-secretase 1), CAPS (Cryopyrin-associated periodic syndromes), CARD (Caspase activating recruitment domain), cIAP (Cytosolic inhibitor of apoptosis protein), CLR (C-type lectin receptors), CNS (Central nervous system), CSF (Cerebrospinal fluid), DAMP (Danger-associated molecular pattern), Eth-D2 (Ethidium homodimer-2), GOS (Glasgow Outcome Scale), HIV (Human immunodeficiency virus), HSP (Heat shock protein), IL (Interleukin), NLR (NOD-like receptor), NOD (Nucleotide oligomerization domain), PAMP (Pathogen-associated molecular pattern), PRR (Pattern recognition receptor), RLR (RIG-1-like receptors), rtPA (Recombinant tissue plasminogen activator), SGT1 (suppressor of G2 allele of skp1), TLR (Toll-like receptors), XIAP (X-linked inhibitor of apoptosis protein)
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      References

        • Martinon F.
        • Burns K.
        • Tschopp J.
        The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
        Mol Cell. 2002; 10: 417-426
        • Piazza O.
        • Scarpati G.
        • Cotena S.
        • Lonardo M.
        • Tufano R.
        Thrombin antithrombin complex and IL-18 serum levels in stroke patients.
        Neurol Int. 2010; 2: e1
        • Jefferis B.J.
        • Whincup P.H.
        • Welsh P.
        • et al.
        Prospective study of IL-18 and risk of MI and stroke in men and women aged 60-79 years: a nested case-control study.
        Cytokine. 2013; 61: 513-520
        • Cvetkovic J.T.
        • Wiklund P.G.
        • Ahmed E.
        • Weinehall L.
        • Hallmans G.
        • Lefvert A.K.
        Polymorphisms of IL-1beta, IL-1Ra, and TNF-alpha genes: a nested case-control study of their association with risk for stroke.
        J Stroke Cerebrovasc Dis. 2005; 14: 29-35
        • Hutchinson P.J.
        • O'Connell M.T.
        • Rothwell N.J.
        • et al.
        Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra.
        J Neurotrauma. 2007; 24: 1545-1557
        • Ciaramella A.
        • Della Vedova C.
        • Salani F.
        • et al.
        Increased levels of serum IL-18 are associated with the long-term outcome of severe traumatic brain injury.
        Neuroimmunomodulation. 2014; 21: 8-12
        • Kostulas N.
        • Pelidou S.H.
        • Kivisakk P.
        • Kostulas V.
        • Link H.
        Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study.
        Stroke. 1999; 30: 2174-2179
        • Yatsiv I.
        • Morganti-Kossmann M.C.
        • Perez D.
        • et al.
        Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.
        J Cereb Blood Flow Metab. 2002; 22: 971-978
        • Bossu P.
        • Salani F.
        • Cacciari C.
        • et al.
        Disease outcome, alexithymia and depression are differently associated with serum IL-18 levels in acute stroke.
        Curr Neurovasc Res. 2009; 6: 163-170
        • Vigano E.
        • Mortellaro A.
        Caspase-11: the driving factor for noncanonical inflammasomes.
        Eur J Immunol. 2013; 43: 2240-2245
        • Adamczak S.E.
        • de Rivero Vaccari J.P.
        • Dale G.
        • et al.
        Pyroptotic neuronal cell death mediated by the AIM2 inflammasome.
        J Cereb Blood Flow Metab. 2014; 34: 621-629
        • de Rivero Vaccari J.P.
        • Lotocki G.
        • Alonso O.F.
        • Bramlett H.M.
        • Dietrich W.D.
        • Keane R.W.
        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
        • de Rivero Vaccari J.P.
        • Lotocki G.
        • Marcillo A.E.
        • Dietrich W.D.
        • Keane R.W.
        A molecular platform in neurons regulates inflammation after spinal cord injury.
        J Neurosci. 2008; 28: 3404-3414
        • Minkiewicz J.
        • de Rivero Vaccari J.P.
        • Keane R.W.
        Human astrocytes express a novel NLRP2 inflammasome.
        Glia. 2013; 61: 1113-1121
        • Beug S.T.
        • Cheung H.H.
        • LaCasse E.C.
        • Korneluk R.G.
        Modulation of immune signalling by inhibitors of apoptosis.
        Trends Immunol. 2012; 33: 535-545
        • Abulafia D.P.
        • de Rivero Vaccari J.P.
        • Lozano J.D.
        • Lotocki G.
        • Keane R.W.
        • Dietrich W.D.
        Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice.
        J Cereb Blood Flow Metab. 2009; 29: 534-544
        • Madouri F.
        • Guillou N.
        • Fauconnier L.
        • et al.
        Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation.
        J Mol Cell Biol. 2015; ([Epub ahead of print])
        • Gadani S.P.
        • Walsh J.T.
        • Smirnov I.
        • Zheng J.
        • Kipnis J.
        The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury.
        Neuron. 2015; 85: 703-709
        • Bianchi M.E.
        DAMPs, PAMPs and alarmins: all we need to know about danger.
        J Leukoc Biol. 2007; 81: 1-5
        • Tang D.
        • Kang R.
        • Coyne C.B.
        • Zeh H.J.
        • Lotze M.T.
        PAMPs and DAMPs: signal 0s that spur autophagy and immunity.
        Immunol Rev. 2012; 249: 158-175
        • de Rivero Vaccari J.C.
        • Brand 3rd, F.J.
        • Berti A.F.
        • Alonso O.F.
        • Bullock M.R.
        • de Rivero Vaccari J.P.
        Mincle signaling in the innate immune response after traumatic brain injury.
        J Neurotrauma. 2015; 32: 228-236
        • Kigerl K.A.
        • de Rivero Vaccari J.P.
        • Dietrich W.D.
        • Popovich P.G.
        • Keane R.W.
        Pattern recognition receptors and central nervous system repair.
        Exp Neurol. 2014; 258: 5-16
        • Latz E.
        • Xiao T.S.
        • Stutz A.
        Activation and regulation of the inflammasomes.
        Nat Rev Immunol. 2013; 13: 397-411
        • Lane T.
        • Flam B.
        • Lockey R.
        • Kolliputi N.
        TXNIP shuttling: missing link between oxidative stress and inflammasome activation.
        Front Physiol. 2013; 4: 50
        • Silverman W.R.
        • de Rivero Vaccari J.P.
        • Locovei S.
        • et al.
        The pannexin 1 channel activates the inflammasome in neurons and astrocytes.
        J Biol Chem. 2009; 284: 18143-18151
        • de Rivero Vaccari J.P.
        • Bastien D.
        • Yurcisin G.
        • et al.
        P2X4 receptors influence inflammasome activation after spinal cord injury.
        J Neurosci. 2012; 32: 3058-3066
        • Varma A.K.
        • Das A.
        • Gt W.
        • et al.
        Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers.
        Neurochem Res. 2013; 38: 895-905
        • Ackery A.
        • Tator C.
        • Krassioukov A.
        A global perspective on spinal cord injury epidemiology.
        J Neurotrauma. 2004; 21: 1355-1370
        • Tator C.H.
        Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations.
        Neurosurgery. 2006; 59: 957-982
        • Coleman W.P.
        • Benzel D.
        • Cahill D.W.
        • et al.
        A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury.
        J Spinal Disord. 2000; 13: 185-199
        • Dumont R.J.
        • Verma S.
        • Okonkwo D.O.
        • et al.
        Acute spinal cord injury, part II: contemporary pharmacotherapy.
        Clin Neuropharmacol. 2001; 24: 265-279
        • Kan E.M.
        • Ling E.A.
        • Lu J.
        Stem cell therapy for spinal cord injury.
        Curr Med Chem. 2010; 17: 4492-4510
        • Pointillart V.
        • Petitjean M.E.
        • Wiart L.
        • et al.
        Pharmacological therapy of spinal cord injury during the acute phase.
        Spinal Cord. 2000; 38: 71-76
        • Fehlings M.G.
        • Baptiste D.C.
        Current status of clinical trials for acute spinal cord injury.
        Injury. 2005; 36: B113-B122
        • Faden A.I.
        Opiate-receptor antagonists, thyrotropin-releasing hormone (TRH), and TRH analogs in the treatment of spinal cord injury.
        Cent Nerv Syst Trauma. 1987; 4: 217-226
        • Chinnock P.
        • Roberts I.
        Gangliosides for acute spinal cord injury.
        Cochrane Database Syst Rev. 2005; : CD004444
        • Fehlings M.G.
        • Theodore N.
        • Harrop J.
        • et al.
        A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.
        J Neurotrauma. 2011; 28: 787-796
        • Ibrahim E.
        • Castle S.M.
        • Aballa T.C.
        • et al.
        Neutralization of ASC improves sperm motility in men with spinal cord injury.
        Hum Reprod. 2014; 29: 2368-2373
        • Zhang X.
        • Ibrahim E.
        • de Rivero Vaccari J.P.
        • et al.
        Involvement of the inflammasome in abnormal semen quality of men with spinal cord injury.
        Fertil Steril. 2013; 99: 118-124
        • Maas A.I.
        • Stocchetti N.
        • Bullock R.
        Moderate and severe traumatic brain injury in adults.
        Lancet Neurol. 2008; 7: 728-741
        • Hoge C.W.
        • McGurk D.
        • Thomas J.L.
        • Cox A.L.
        • Engel C.C.
        • Castro C.A.
        Mild traumatic brain injury in U.S. soldiers returning from Iraq.
        N Engl J Med. 2008; 358: 453-463
        • Bramlett H.M.
        • Dietrich W.D.
        Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies.
        Prog Brain Res. 2007; 161: 125-141
        • Kabadi S.V.
        • Faden A.I.
        Neuroprotective strategies for traumatic brain injury: improving clinical translation.
        Int J Mol Sci. 2014; 15: 1216-1236
        • McIntosh T.K.
        • Smith D.H.
        • Garde E.
        Therapeutic approaches for the prevention of secondary brain injury.
        Eur J Anaesthesiol. 1996; 13: 291-309
        • Faden A.I.
        Neuroprotection and traumatic brain injury: theoretical option or realistic proposition.
        Curr Opin Neurol. 2002; 15: 707-712
        • Stein D.G.
        Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update.
        Neuroscience. 2011; 191: 101-106
        • Wright D.W.
        • Kellermann A.L.
        • Hertzberg V.S.
        • et al.
        ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.
        Ann Emerg Med. 2007; 49: 391-402.e1–e2
        • Ponce L.L.
        • Navarro J.C.
        • Ahmed O.
        • Robertson C.S.
        Erythropoietin neuroprotection with traumatic brain injury.
        Pathophysiology. 2013; 20: 31-38
        • Nirula R.
        • Diaz-Arrastia R.
        • Brasel K.
        • Weigelt J.A.
        • Waxman K.
        Safety and efficacy of erythropoietin in traumatic brain injury patients: a pilot randomized trial.
        Crit Care Res Pract. 2010; : 1-5
        • Marion D.W.
        Decompressive craniectomy in diffuse traumatic brain injury.
        Lancet Neurol. 2011; 10: 497-498
        • Dietrich W.D.
        • Bramlett H.M.
        The evidence for hypothermia as a neuroprotectant in traumatic brain injury.
        Neurotherapeutics. 2010; 7: 43-50
        • Yokobori S.
        • Hosein K.
        • Burks S.
        • Sharma I.
        • Gajavelli S.
        • Bullock R.
        Biomarkers for the clinical differential diagnosis in traumatic brain injury—a systematic review.
        CNS Neurosci Ther. 2013; 19: 556-565
        • Wible E.F.
        • Laskowitz D.T.
        Statins in traumatic brain injury.
        Neurotherapeutics. 2010; 7: 62-73
        • Mazzeo A.T.
        • Alves O.L.
        • Gilman C.B.
        • et al.
        Brain metabolic and hemodynamic effects of cyclosporin A after human severe traumatic brain injury: a microdialysis study.
        Acta Neurochir. 2008; 150 (discussion 31): 1019-1031
        • Liu H.D.
        • Li W.
        • Chen Z.R.
        • et al.
        Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model.
        Neurochem Res. 2013; 38: 2072-2083
        • Adamczak S.
        • Dale G.
        • de Rivero Vaccari J.P.
        • Bullock M.R.
        • Dietrich W.D.
        • Keane R.W.
        Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article.
        J Neurosurg. 2012; 117: 1119-1125
        • Tomura S.
        • de Rivero Vaccari J.P.
        • Keane R.W.
        • Bramlett H.M.
        • Dietrich W.D.
        Effects of therapeutic hypothermia on inflammasome signaling after traumatic brain injury.
        J Cereb Blood Flow Metab. 2012; 32: 1939-1947
        • Majid A.
        Neuroprotection in stroke: past, present, and future.
        ISRN Neurol. 2014; 2014: 515716
        • Tymianski M.
        Novel approaches to neuroprotection trials in acute ischemic stroke.
        Stroke. 2013; 44: 2942-2950
        • Reed S.D.
        • Cramer S.C.
        • Blough D.K.
        • Meyer K.
        • Jarvik J.G.
        Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals.
        Stroke. 2001; 32: 1832-1840
        • Noorian A.R.
        • Gupta R.
        • Nogueira R.G.
        Stenting of complete vertebral artery ostial occlusion in a patient with medically refractory vertebrobasilar ischemia.
        J Neurointerv Surg. 2012; 4: e31
        • O'Collins V.E.
        • Macleod M.R.
        • Donnan G.A.
        • Horky L.L.
        • van der Worp B.H.
        • Howells D.W.
        1,026 Experimental treatments in acute stroke.
        Ann Neurol. 2006; 59: 467-477
        • Saver J.L.
        • Starkman S.
        • Eckstein M.
        • et al.
        Prehospital use of magnesium sulfate as neuroprotection in acute stroke.
        N Engl J Med. 2015; 372: 528-536
        • Dorhout Mees S.M.
        • MASH-II Study Group
        Magnesium in aneurysmal subarachnoid hemorrhage (MASH II) phase III clinical trial MASH-II study group.
        Int J Stroke. 2008; 3: 63-65
        • Davalos A.
        • Alvarez-Sabin J.
        • Castillo J.
        • et al.
        Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial).
        Lancet. 2012; 380: 349-357
        • Heiss W.D.
        • Brainin M.
        • Bornstein N.M.
        • Tuomilehto J.
        • Hong Z.
        Cerebrolysin acute stroke treatment in Asia I. Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial.
        Stroke. 2012; 43: 630-636
        • Liu X.
        • Wang L.
        • Wen A.
        • et al.
        Ginsenoside-Rd improves outcome of acute ischaemic stroke—a randomized, double-blind, placebo-controlled, multicenter trial.
        Eur J Neurol. 2012; 19: 855-863
        • Mohamed I.N.
        • Ishrat T.
        • Fagan S.C.
        • El-Remessy A.B.
        Role of inflammasome activation in the pathophysiology of vascular diseases of the neurovascular unit.
        Antioxid Redox Signal. 2014; 22: 1188-1206
        • Fann D.Y.
        • Lee S.Y.
        • Manzanero S.
        • et al.
        Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke.
        Cell Death Dis. 2013; 4: e790
        • Ma Q.
        • Chen S.
        • Hu Q.
        • Feng H.
        • Zhang J.H.
        • Tang J.
        NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage.
        Ann Neurol. 2014; 75: 209-219
        • Mayor A.
        • Martinon F.
        • De Smedt T.
        • Petrilli V.
        • Tschopp J.
        A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.
        Nat Immunol. 2007; 8: 497-503
        • Bryan N.B.
        • Dorfleutner A.
        • Kramer S.J.
        • Yun C.
        • Rojanasakul Y.
        • Stehlik C.
        Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes.
        J Inflamm. 2010; 7: 23
        • Franklin B.S.
        • Bossaller L.
        • De Nardo D.
        • et al.
        The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation.
        Nat Immunol. 2014; 15: 727-737
        • Fernandes-Alnemri T.
        • Wu J.
        • Yu J.W.
        • et al.
        The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation.
        Cell Death Differ. 2007; 14: 1590-1604
        • Fink S.L.
        • Bergsbaken T.
        • Cookson B.T.
        Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms.
        Proc Natl Acad Sci U S A. 2008; 105: 4312-4317
      1. Adamczak SE. Molecular recognition of DNA by the AIM2 inflammasome induces neuronal pyroptosis: implications in infection and host tissue damage. Open Access Dissertations; 2012 (Paper 854).

        • Baroja-Mazo A.
        • Martin-Sanchez F.
        • Gomez A.I.
        • et al.
        The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response.
        Nat Immunol. 2014; 15: 738-748
        • de Rivero Vaccari J.P.
        • Brand 3rd, F.
        • Adamczak S.
        • et al.
        Exosome-mediated inflammasome signaling after central nervous system injury.
        J Neurochem. 2015; ([Epub ahead of print])
        • Alvarez-Erviti L.
        • Seow Y.
        • Yin H.
        • Betts C.
        • Lakhal S.
        • Wood M.J.
        Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.
        Nat Biotechnol. 2011; 29: 341-345
        • Fruhbeis C.
        • Frohlich D.
        • Kuo W.P.
        • et al.
        Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication.
        PLoS Biol. 2013; 11: e1001604
        • Pant S.
        • Hilton H.
        • Burczynski M.E.
        The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities.
        Biochem Pharmacol. 2012; 83: 1484-1494
        • Block M.L.
        • Hong J.S.
        Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism.
        Prog Neurobiol. 2005; 76: 77-98
        • Dirnagl U.
        • Iadecola C.
        • Moskowitz M.A.
        Pathobiology of ischaemic stroke: an integrated view.
        Trends Neurosci. 1999; 22: 391-397
        • Lucas S.M.
        • Rothwell N.J.
        • Gibson R.M.
        The role of inflammation in CNS injury and disease.
        Br J Pharmacol. 2006; 147: S232-S240
        • Coll R.C.
        • Robertson A.
        • Butler M.
        • Cooper M.
        • O'Neill L.A.
        The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes.
        PLoS One. 2011; 6: e29539
        • Shi Q.J.
        • Xiao L.
        • Zhao B.
        • et al.
        Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats.
        Brain Res. 2012; 1484: 57-67
        • Lenz Q.F.
        • Arroyo D.S.
        • Temp F.R.
        • et al.
        Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood-brain barrier dysfunction.
        Neuroscience. 2014; 277: 859-871
        • Cohen S.B.
        • Moreland L.W.
        • Cush J.J.
        • et al.
        A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.
        Ann Rheum Dis. 2004; 63: 1062-1068
        • Smith C.J.
        • Emsley H.C.
        • Udeh C.T.
        • et al.
        Interleukin-1 receptor antagonist reverses stroke-associated peripheral immune suppression.
        Cytokine. 2012; 58: 384-389
        • Greenhalgh A.D.
        • Galea J.
        • Denes A.
        • Tyrrell P.J.
        • Rothwell N.J.
        Rapid brain penetration of interleukin-1 receptor antagonist in rat cerebral ischaemia: pharmacokinetics, distribution, protection.
        Br J Pharmacol. 2010; 160: 153-159
        • Banwell V.
        • Sena E.S.
        • Macleod M.R.
        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
        • Kuemmerle-Deschner J.B.
        • Ramos E.
        • Blank N.
        • et al.
        Canakinumab (ACZ885, a fully human IgG1 anti-IL-1beta mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS).
        Arthritis Res Ther. 2011; 13: R34
        • Abbate A.
        • Van Tassell B.W.
        • Biondi-Zoccai G.G.
        Blocking interleukin-1 as a novel therapeutic strategy for secondary prevention of cardiovascular events.
        BioDrugs. 2012; 26: 217-233
        • Clausen F.
        • Hanell A.
        • Bjork M.
        • et al.
        Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice.
        Eur J Neurosci. 2009; 30: 385-396
        • Clausen F.
        • Hanell A.
        • Israelsson C.
        • et al.
        Neutralization of interleukin-1beta reduces cerebral edema and tissue loss and improves late cognitive outcome following traumatic brain injury in mice.
        Eur J Neurosci. 2011; 34: 110-123
        • Ridker P.M.
        • Thuren T.
        • Zalewski A.
        • Libby P.
        Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).
        Am Heart J. 2011; 162: 597-605
        • Mistry P.
        • Reid J.
        • Pouliquen I.
        • et al.
        Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin-18 mAb GSK1070806 in healthy and obese subjects.
        Int J Clin Pharmacol Ther. 2014; 52: 867-879
        • Rudolphi K.
        • Gerwin N.
        • Verzijl N.
        • van der Kraan P.
        • van den Berg W.
        Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis.
        Osteoarthritis Cartilage. 2003; 11: 738-746
        • Siegmund B.
        • Zeitz M.
        Pralnacasan (vertex pharmaceuticals).
        IDrugs. 2003; 6: 154-158
        • Ross J.
        • Brough D.
        • Gibson R.M.
        • Loddick S.A.
        • Rothwell N.J.
        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
        • Noe F.M.
        • Polascheck N.
        • Frigerio F.
        • et al.
        Pharmacological blockade of IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy.
        Neurobiol Dis. 2013; 59: 183-193
        • Dong L.
        • Qiao H.
        • Zhang X.
        • et al.
        Parthenolide is neuroprotective in rat experimental stroke model: downregulating NF-kappaB, phospho-p38MAPK, and caspase-1 and ameliorating BBB permeability.
        Mediators Inflamm. 2013; 2013: 370804
        • Guzman M.L.
        • Rossi R.M.
        • Neelakantan S.
        • et al.
        An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells.
        Blood. 2007; 110: 4427-4435
        • Mariathasan S.
        • Weiss D.S.
        • Newton K.
        • et al.
        Cryopyrin activates the inflammasome in response to toxins and ATP.
        Nature. 2006; 440: 228-232
        • Ashcroft F.M.
        ATP-sensitive potassium channelopathies: focus on insulin secretion.
        J Clin Invest. 2005; 115: 2047-2058
        • Lamkanfi M.
        • Mueller J.L.
        • Vitari A.C.
        • et al.
        Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
        J Cell Biol. 2009; 187: 61-70
        • Neufeld N.D.
        • Harris M.
        • Corbo L.M.
        • Koduri A.
        Effect of glyburide in type II diabetes mellitus. Studies of monocyte membrane fluidity, lipid composition, and insulin binding.
        Diabetes. 1987; 36: 1351-1355
        • Marchetti C.
        • Chojnacki J.
        • Toldo S.
        • et al.
        A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse.
        J Cardiovasc Pharmacol. 2014; 63: 316-322
        • Coll R.C.
        • Robertson A.A.
        • Chae J.J.
        • et al.
        A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.
        Nat Med. 2015; 21: 248-255
        • Keystone E.C.
        • Wang M.M.
        • Layton M.
        • Hollis S.
        • McInnes I.B.
        • Team D.C.S.
        Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine.
        Ann Rheum Dis. 2012; 71: 1630-1635
        • Ozaki E.
        • Campbell M.
        • Doyle S.L.
        Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives.
        J Inflamm Res. 2015; 8: 15-27
        • North R.A.
        • Jarvis M.F.
        P2X receptors as drug targets.
        Mol Pharmacol. 2013; 83: 759-769