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Review Article

Potential molecular targets of peroxynitrite in mediating blood–brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment

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Pages 1220-1239 | Received 02 Jan 2018, Accepted 05 Sep 2018, Published online: 23 Nov 2018

References

  • Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34(2):185–199.
  • Henninger N, Fisher M. Extending the time window for endovascular and pharmacological reperfusion. Transl Stroke Res. 2016;7(4):284–293.
  • Fan X, Jiang Y, Yu Z, et al. Combination approaches to attenuate hemorrhagic transformation after tPA thrombolytic therapy in patients with poststroke hyperglycemia/diabetes. Adv Pharmacol. 2014;71:391–410.
  • Kanazawa M, Takahashi T, Nishizawa M, et al. Therapeutic strategies to attenuate hemorrhagic transformation after tissue plasminogen activator treatment for acute ischemic stroke. J Atheroscler Thromb. 2017;24(3):240–253.
  • Ballabh P, Braun A, Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16(1):1–13.
  • Dirnagl U. Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann NY Acad Sci. 2012;1268(1):21–25.
  • del Zoppo GJ. Stroke and neurovascular protection. N Engl J Med. 2006;354(6):553–555.
  • Knecht T, Story J, Liu J, et al. Adjunctive therapy approaches for ischemic stroke: innovations to expand time window of treatment. Int J Mol Sci. 2017;18(12):2756–2773.
  • Peña ID, Borlongan C, Shen G, et al. Strategies to extend thrombolytic time window for ischemic stroke treatment: an unmet clinical need. J Stroke. 2017;19(1):50–60.
  • Wang X, Tsuji K, Lee SR, et al. Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. Stroke. 2004;35(11 Suppl 1):2726–2730.
  • Lapchak PA. Hemorrhagic transformation following ischemic stroke: significance, causes, and relationship to therapy and treatment. Curr Neurol Neurosci Rep. 2002;2(1):38–43.
  • Zhang L, Zhang ZG, Chopp M. The neurovascular unit and combination treatment strategies for stroke. Trends Pharmacol Sci. 2012;33(8):415–422.
  • Granger DN, Kvietys PR. Reperfusion therapy – what’s with the obstructed, leaky and broken capillaries? Pathophysiology. 2017;24(4):213–228.
  • Asahi M, Asahi K, Wang X, et al. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2000;20(3):452–457.
  • Yagi K, Kitazato KT, Uno M, et al. Edaravone, a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke. 2009;40(2):626–631.
  • Chen HS, Chen X, Li WT, et al. Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery. Acta Pharmacol Sin. 2018;39(5):669–682.
  • Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke. 2000;31(12):3034–3040.
  • Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33(3):831–836.
  • Zhang Y, Fan F, Zeng G, et al. Temporal analysis of blood–brain barrier disruption and cerebrospinal fluid matrix metalloproteinases in rhesus monkeys subjected to transient ischemic stroke. J Cereb Blood Flow Metab. 2017;37(8):2963–2974.
  • Yepes M, Sandkvist M, Moore EG, et al. Tissue-type plasminogen activator induces opening of the blood–brain barrier via the LDL receptor–related protein. J Clin Invest. 2003;112(10):1533–1540.
  • Hu K, Yang J, Tanaka S, et al. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J Biol Chem. 2006;281(4):2120–2127.
  • Kanazawa M, Igarashi H, Kawamura K, et al. Inhibition of VEGF signaling pathway attenuates hemorrhage after tPA treatment. J Cereb Blood Flow Metab. 2011;31(6):1461–1474.
  • Chi OZ, Hunter C, Liu X, et al. Effects of anti-VEGF antibody on blood–brain barrier disruption in focal cerebral ischemia. Exp Neurol. 2007;204(1):283–287.
  • Su EJ, Fredriksson L, Schielke GP, et al. Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke. J Thromb Haemost. 2009;7(Suppl 1):155–158.
  • Fredriksson L, Li H, Fieber C, et al. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J. 2004;23(19):3793–3802.
  • Su EJ, Fredriksson L, Geyer M, et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood–brain barrier integrity during ischemic stroke. Nat Med. 2008;14(7):731–737.
  • Cheng T, Petraglia AL, Li Z, et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006;12(11):1278–1285.
  • Wang Y, Zhao Z, Chow N, et al. Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats. Stroke. 2013;44(12):3529–3536.
  • Wang Y, Zhang Z, Chow N, et al. An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. Stroke. 2012;43(9):2444–2449.
  • Liu Y, Zheng Y, Karatas H, et al. 12/15-lipoxygenase inhibition or knockout reduces warfarin-associated hemorrhagic transformation after experimental stroke. Stroke. 2017;48(2):445–451.
  • Yigitkanli K, Zheng Y, Pekcec A, et al. Increased 12/15-lipoxygenase leads to widespread brain injury following global cerebral ischemia. Transl Stroke Res. 2017;8(2):194–202.
  • Chen HS, Qi SH, Shen JG. One-compound-multi-target: combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol. 2017;15(1):134–156.
  • Chen H, Guan B, Shen J. Targeting ONOO-/HMGB1/MMP-9 signaling cascades: potential for drug development from Chinese medicine to attenuate ischemic brain injury and hemorrhagic transformation induced by thrombolytic treatment. Integrative Med Int. 2016;3(1–2)32–52.
  • Chen XM, Chen HS, Xu MJ, et al. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury. Acta Pharmacol Sin. 2013;34(1):67–77.
  • Shen J, Ma S, Chan P, et al. Nitric oxide down-regulates caveolin-1 expression in rat brains during focal cerebral ischemia and reperfusion injury. J Neurochem. 2006;96(4):1078–1089.
  • McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. 1985;312(3):159–163.
  • Crow JP, Beckman JS. The role of peroxynitrite in nitric oxide-mediated toxicity. Curr Top Microbiol Immunol. 1995;196:57–73.
  • Kuhn DM, Sakowski SA, Sadidi M, et al. Nitrotyrosine as a marker for peroxynitrite-induced neurotoxicity: the beginning or the end of the end of dopamine neurons? J Neurochem. 2004;89(3):529–536.
  • Suzuki M, Tabuchi M, Ikeda M, et al. Concurrent formation of peroxynitrite with the expression of inducible nitric oxide synthase in the brain during middle cerebral artery occlusion and reperfusion in rats. Brain Res. 2002;951(1):113–120.
  • Takizawa S, Fukuyama N, Hirabayashi H, et al. Dynamics of nitrotyrosine formation and decay in rat brain during focal ischemia-reperfusion. J Cereb Blood Flow Metab. 1999;19(6):667–672.
  • Gürsoy-Ozdemir Y, Can A, Dalkara T. Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke. 2004;35(6):1449–1453.
  • Chen X, Chen H, Deng R, et al. Pros and cons of current approaches for detecting peroxynitrite and their applications. Biomed J. 2014;37(3):120–126.
  • Yang D, Sun ZN, Peng T, et al. Synthetic fluorescent probes for imaging of peroxynitrite and hypochlorous acid in living cells. Methods Mol Biol. 2010;591:93–103.
  • Yang D, Wang HL, Sun ZN, et al. A highly selective fluorescent probe for the detection and imaging of peroxynitrite in living cells. J Am Chem Soc. 2006;128(18):6004–6005.
  • Peng T, Chen X, Gao L, et al. A rationally designed rhodamine-based fluorescent probe for molecular imaging of peroxynitrite in live cells and tissues. Chem Sci. 2016;7(8):5407–5413.
  • Chen H, Guan B, Chen X, et al. Baicalin attenuates blood–brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: involvement of ONOO(-)-MMP-9 pathway. Transl Stroke Res. 2017;9(5):515–529.
  • Gong J, Sun F, Li Y, et al. Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway. Neuropharmacology. 2015;91:123–134.
  • Gao L, Chen X, Peng T, et al. Caveolin-1 protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death. Free Radic Biol Med. 2016;95(Suppl C):209–215.
  • Chen HS, Chen XM, Feng JH, et al. Peroxynitrite decomposition catalyst reduces delayed thrombolysis-induced hemorrhagic transformation in ischemia-reperfused rat brains. CNS Neurosci Ther. 2015;21(7):585–590.
  • Dhar A, Kaundal RK, Sharma SS. Neuroprotective effects of FeTMPyP: a peroxynitrite decomposition catalyst in global cerebral ischemia model in gerbils. Pharmacol Res. 2006;54(4):311–316.
  • Thiyagarajan M, Kaul CL, Sharma SS. Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats. Br J Pharmacol. 2004;142(5):899–911.
  • Romanos E, Planas AM, Amaro S, et al. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007;27(1):14–20.
  • Li R, Huang C, Chen J, et al. The role of uric acid as a potential neuroprotectant in acute ischemic stroke: a review of literature. Neurol Sci. 2015;36(7):1097–1103.
  • Liu X, Liu M, Chen M, et al. Serum uric acid is neuroprotective in Chinese patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. J Stroke Cerebrovasc Dis. 2015;24(5):1080–1086.
  • Lee SH, Heo SH, Kim JH, et al. Effects of uric acid levels on outcome in severe ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator. Eur Neurol. 2014;71(3–4):132–139.
  • Wang Z, Lin Y, Liu Y, et al. Serum uric acid levels and outcomes after acute ischemic stroke. Mol Neurobiol. 2016;53(3):1753–1759.
  • Chamorro Á, Amaro S, Castellanos M, et al. Uric acid therapy improves the outcomes of stroke patients treated with intravenous tissue plasminogen activator and mechanical thrombectomy. Int J Stroke. 2017;12(4):377–382.
  • Takamiya M, Miyamoto Y, Yamashita T, et al. Strong neuroprotection with a novel platinum nanoparticle against ischemic stroke- and tissue plasminogen activator-related brain damages in mice. Neuroscience. 2012;221:47–55.
  • Kilic E, Kilic U, Bahr M, et al. Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo. NeuroDegener Dis. 2005;2(2):49–55.
  • Kilic E, Kilic U, Reiter RJ, et al. Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: role of iNOS and Akt. J Pineal Res. 2005;39(2):151–155.
  • Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007;87(1):315–424.
  • Suofu Y, Clark J, Broderick J, et al. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase activation and neurovascular injury after prolonged cerebral ischemia in rats. J Neurochem. 2010;115(5):1266–1276.
  • Gu Y, Chen J, Shen J. Herbal medicines for ischemic stroke: combating inflammation as therapeutic targets. J Neuroimmun Pharmacol. 2014;9(3):313–339.
  • Chandrashekaran V, Seth RK, Dattaroy D, et al. HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease. Redox Biol. 2017;13:8–19.
  • Qiu J, Xu J, Zheng Y, et al. High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia. Stroke. 2010;41(9):2077–2082.
  • Loukili N, Rosenblatt-Velin N, Li J, et al. Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo. Cardiovasc Res. 2011;89(3):586–594.
  • Ishiguro M, Kawasaki K, Suzuki Y, et al. A Rho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9-related hemorrhagic transformation in mice treated with tissue plasminogen activator. Neuroscience. 2012;220:302–312.
  • Wang W, Li M, Wang Y, et al. GSK-3beta inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/beta-catenin signaling pathway after acute ischemic stroke in rats. Mol Neurobiol. 2016;53(10):7028–7036.
  • Gu Y, Zheng G, Xu M, et al. Caveolin-1 regulates nitric oxide-mediated matrix metalloproteinases activity and blood–brain barrier permeability in focal cerebral ischemia and reperfusion injury. J Neurochem. 2012;120(1):147–156.
  • Shen J, Gu Y. Insights into mechanisms of blood–brain barrier permeability–roles of free radicals, matrix metalloproteinsases, and caveolin-1. In: Laher I. editor. Systems biology of free radicals and antioxidants. Berlin (HD): Springer; 2014. p. 2049–2067.
  • Gu Y, Dee CM, Shen J. Interaction of free radicals, matrix metalloproteinases and caveolin-1 impacts blood–brain barrier permeability. Front Biosci. 2011;3(3):1216–1231.
  • Yang Y, Estrada EY, Thompson JF, et al. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697–709.
  • Chaturvedi M, Kaczmarek L. Mmp-9 inhibition: a therapeutic strategy in ischemic stroke. Mol Neurobiol. 2014;49(1):563–573.
  • Rosell A, Cuadrado E, Ortega-Aznar A, et al. MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39(4):1121–1126.
  • Bauer AT, Bürgers HF, Rabie T, et al. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab. 2010;30(4):837–848.
  • Asahi M, Wang X, Mori T, et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001;21(19):7724–7732.
  • Hu Q, Chen C, Khatibi NH, et al. Lentivirus-mediated transfer of MMP-9 shRNA provides neuroprotection following focal ischemic brain injury in rats. Brain Res. 2011;1367:347–359.
  • Hu Q, Chen C, Yan J, et al. Therapeutic application of gene silencing MMP-9 in a middle cerebral artery occlusion-induced focal ischemia rat model. Exp Neurol. 2009;216(1):35–46.
  • Clark AW, Krekoski CA, Bou SS, et al. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci Lett. 1997;238(1–2):53–56.
  • Rosell A, Ortega-Aznar A, Alvarez-Sabín J, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37(6):1399–1406.
  • Montaner J, Molina CA, Monasterio J, et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003;107(4):598–603.
  • Ramos-Fernandez M, Bellolio MF, Stead LG. Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis. 2011;20(1):47–54.
  • Mishiro K, Ishiguro M, Suzuki Y, et al. A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice. Neuroscience. 2012;205:39–48.
  • Murata Y, Rosell A, Scannevin RH, et al. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008;39(12):3372–3377.
  • Suzuki Y, Nagai N, Umemura K, et al. Stromelysin-1 (MMP-3) is critical for intracranial bleeding after t-PA treatment of stroke in mice. J Thromb Haemost. 2007;5(8):1732–1739.
  • Suzuki Y, Nagai N, Yamakawa K, et al. Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein. Blood. 2009;114(15):3352–3358.
  • Ding R, Feng L, He L, et al. Peroxynitrite decomposition catalyst prevents matrix metalloproteinase-9 activation and neurovascular injury after hemoglobin injection into the caudate nucleus of rats. Neuroscience. 2015;297:182–193.
  • Tan KH, Harrington S, Purcell WM, et al. Peroxynitrite mediates nitric oxide-induced blood–brain barrier damage. Neurochem Res. 2004;29(3):579–587.
  • Okamoto T, Akaike T, Sawa T, et al. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathiolation via disulfide S-oxide formation. J Biol Chem. 2001;276(31):29596–29602.
  • Hafez S, Abdelsaid M, Fagan SC, et al. Peroxynitrite-induced tyrosine nitration contributes to matrix metalloprotease-3 activation: relevance to hyperglycemic ischemic brain injury and tissue plasminogen activator. Neurochem Res. 2018;43(2):259–266.
  • Amaro S, Obach V, Cervera A, et al. Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study. J Neurol. 2009;256(4):651–656.
  • Landsman D, Bustin M. A signature for the HMG-1 box DNA-binding proteins. BioEssays. 1993;15(8):539–546.
  • Muhammad S, Barakat W, Stoyanov S, et al. The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci. 2008;28(46):12023–12031.
  • Goldstein RS, Gallowitsch-Puerta M, Yang L, et al. Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. Shock. 2006;25(6):571–574.
  • Sapojnikova N, Kartvelishvili T, Asatiani N, et al. Correlation between MMP-9 and extracellular cytokine HMGB1 in prediction of human ischemic stroke outcome. Biochim Biophys Acta. 2014;1842(9):1379–1384.
  • Kim JB, Sig Choi J, Yu YM, et al. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci. 2006;26(24):6413–6421.
  • Faraco G, Fossati S, Bianchi ME, et al. High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem. 2007;103(2):590–603.
  • Kim JB, Lim CM, Yu YM, et al. Induction and subcellular localization of high-mobility group box-1 (HMGB1) in the postischemic rat brain. J Neurosci Res. 2008;86(5):1125–1131.
  • Qiu J, Nishimura M, Wang Y, et al. Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab. 2008;28(5):927–938.
  • Liu K, Mori S, Takahashi HK, et al. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. FASEB J. 2007;21(14):3904–3916.
  • Zhang J, Takahashi HK, Liu K, et al. Anti-high mobility group box-1 monoclonal antibody protects the blood–brain barrier from ischemia-induced disruption in rats. Stroke. 2011;42(5):1420–1428.
  • Yang QW, Lu FL, Zhou Y, et al. HMBG1 mediates ischemia—reperfusion injury by TRIF-adaptor independent toll-like receptor 4 signaling. J Cereb Blood Flow Metab. 2011;31(2):593–605.
  • Huang J, Liu B, Yang C, et al. Acute hyperglycemia worsens ischemic stroke-induced brain damage via high mobility group box-1 in rats. Brain Res. 2013;1535(Suppl c):148–155.
  • Ryou MG, Choudhury GR, Winters A, et al. Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation. Brain Res. 2013;1530:66–75.
  • Yang QW, Wang JZ, Li JC, et al. High-mobility group protein box-1 and its relevance to cerebral ischemia. J Cereb Blood Flow Metab. 2010;30(2):243–254.
  • Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4(6):469–478.
  • Gay NJ, Gangloff M. Structure and function of Toll receptors and their ligands. Annu Rev Biochem. 2007;76:141–165.
  • Gesuete R, Kohama SG, Stenzel-Poore MP. Toll-like receptors and ischemic brain injury. J Neuropathol Exp Neurol. 2014;73(5):378–386.
  • Wang Y, Ge P, Zhu Y. TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediators Inflamm. 2013;2013:124614.
  • Hyakkoku K, Hamanaka J, Tsuruma K, et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience. 2010;171(1):258–267.
  • Wang YC, Lin S, Yang QW. Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflamm. 2011;8:134.
  • Lv M, Liu Y, Zhang J, et al. Roles of inflammation response in microglia cell through Toll-like receptors 2/interleukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience. 2011;176:162–172.
  • Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA. 2007;104(34):13798–13803.
  • Cao CX, Yang QW, Lv FL, et al. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. Biochem Biophys Res Commun. 2007;353(2):509–514.
  • Ning R, Chopp M, Yan T, et al. Tissue plasminogen activator treatment of stroke in type-1 diabetes rats. Neuroscience. 2012;222(Suppl c):326–332.
  • García-Culebras A, Palma-Tortosa S, Moraga A, et al. Toll-like Receptor 4 mediates hemorrhagic transformation after delayed tissue plasminogen activator administration in in situ thromboembolic stroke. Stroke. 2017;48(6):1695–1699.
  • Lehnardt S, Lehmann S, Kaul D, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J Neuroimmunol. 2007;190(1–2):28–33.
  • Hua F, Ma J, Ha T, et al. Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J Neuroimmunol. 2007;190(1–2):101–111.
  • Caso JR, Pradillo JM, Hurtado O, et al. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 2007;115(12):1599–1608.
  • Gill R, Tsung A, Billiar T. Linking oxidative stress to inflammation: toll-like receptors. Free Radic Biol Med. 2010;48(9):1121–1132.
  • Janko C, Filipović M, Munoz LE, et al. Redox modulation of HMGB1-related signaling. Antioxid Redox Signal. 2014;20(7):1075–1085.
  • Tang D, Kang R, Zeh HJ, 3rd, et al. High-mobility group box 1, oxidative stress, and disease. Antioxid Redox Signal. 2011;14(7):1315–1335.
  • Hoppe G, Talcott KE, Bhattacharya SK, et al. Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006;312(18):3526–3538.
  • Tang D, Billiar TR, Lotze MT. A Janus tale of two active high mobility group box 1 (HMGB1) redox states. Mol Med. 2012;18(1):1360–1362.
  • Urbonaviciute V, Meister S, Fürnrohr BG, et al. Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis. Autoimmunity. 2009;42(4):305–307.
  • Tang D, Kang R, Cheh CW, et al. HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 2010;29(38):5299–5310.
  • Kikuchi K, Kawahara K, Tancharoen S, et al. The free radical scavenger edaravone rescues rats from cerebral infarction by attenuating the release of high-mobility group box-1 in neuronal cells. J Pharmacol Exp Ther. 2009;329(3):865–874.
  • Wang H, Liu D. Baicalin inhibits high-mobility group box 1 release and improves survival in experimental sepsis. Shock. 2014;41(4):324–330.
  • Xu M, Chen X, Gu Y, et al. Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitrite-mediated neurotoxicity in cerebral ischemia-reperfusion injury. J Ethnopharmacol. 2013;150(1):116–124.
  • Das S, Alhasson F, Dattaroy D, et al. NADPH oxidase-derived peroxynitrite drives inflammation in mice and human nonalcoholic steatohepatitis via TLR4-lipid raft recruitment. Am J Pathol. 2015;185(7):1944–1957.
  • Sappington PL, Yang R, Yang H, et al. HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology. 2002;123(3):790–802.
  • Fan J, Li Y, Levy RM, et al. Hemorrhagic shock induces NAD (P) H oxidase activation in neutrophils: role of HMGB1-TLR4 signaling. J Immunol. 2007;178(10):6573–6580.
  • Tsung A, Klune JR, Zhang X, et al. HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med. 2007;204(12):2913–2923.
  • Park HS, Jung HY, Park EY, et al. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004;173(6):3589–3593.
  • Takahashi K, Pieper AA, Croul SE, et al. Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. Brain Res. 1999;829(1–2):46–54.
  • Ikeda Y, Hokamura K, Kawai T, et al. Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model. Brain Res. 2005;1060(1–2):73–80.
  • Narasimhan P, Fujimura M, Noshita N, et al. Role of superoxide in poly(ADP-ribose) polymerase upregulation after transient cerebral ischemia. Brain Res Mol Brain Res. 2003;113(1–2):28–36.
  • Zhang R, Tang S, Huang W, et al. Protection of the brain following cerebral ischemia through the attenuation of PARP-1-induced neurovascular unit damage in rats. Brain Res. 2015;1624:9–18.
  • Endres M, Scott G, Namura S, et al. Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion. Neurosci Lett. 1998;248(1):41–44.
  • Besson VC, Margaill I, Plotkine M, et al. Deleterious activation of poly(ADP-ribose)polymerase-1 in brain after in vivo oxidative stress. Free Radic Res. 2003;37(11):1201–1208.
  • Zhang J, Dawson VL, Dawson TM, et al. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science. 1994;263(5147):687–689.
  • Virág L, Szabó E, Gergely P, et al. Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett. 2003;140–141:113–124.
  • Skaper SD. Poly(ADP-ribose) polymerase-1 in acute neuronal death and inflammation: a strategy for neuroprotection. Ann NY Acad Sci. 2003;993:217–28; discussion 287.
  • Sharma SS, Munusamy S, Thiyagarajan M, et al. Neuroprotective effect of peroxynitrite decomposition catalyst and poly(adenosine diphosphate-ribose) polymerase inhibitor alone and in combination in rats with focal cerebral ischemia. J Neurosurg. 2004;101(4):669–675.
  • Eliasson MJ, Sampei K, Mandir AS, et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997;3(10):1089–1095.
  • Mandir AS, Poitras MF, Berliner AR, et al. NMDA but not non-NMDA excitotoxicity is mediated by poly(ADP-ribose) polymerase. J Neurosci. 2000;20(21):8005–8011.
  • Endres M, Wang ZQ, Namura S, et al. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab. 1997;17(11):1143–1151.
  • Tokime T, Nozaki K, Sugino T, et al. Enhanced poly(ADP-ribosyl)ation after focal ischemia in rat brain. J Cereb Blood Flow Metab. 1998;18(9):991–997.
  • Abdelkarim GE, Gertz K, Harms C, et al. Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. Int J Mol Med. 2001;7(3):255–260.
  • Egi Y, Matsuura S, Maruyama T, et al. Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia. Brain Res. 2011;1389:169–176.
  • Kaundal RK, Shah KK, Sharma SS. Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. Life Sci. 2006;79(24):2293–2302.
  • Matsuura S, Egi Y, Yuki S, et al. MP-124, a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, ameliorates ischemic brain damage in a non-human primate model. Brain Res. 2011;1410:122–131.
  • Ding Y, Zhou Y, Lai Q, et al. Long-term neuroprotective effect of inhibiting poly(ADP-ribose) polymerase in rats with middle cerebral artery occlusion using a behavioral assessment. Brain Res. 2001;915(2):210–217.
  • Kim Y, Kim YS, Kim HY, et al. Early treatment with poly(ADP-ribose) Polymerase-1 inhibitor (JPI-289) reduces infarct volume and improves long-term behavior in an animal model of ischemic stroke. Mol Neurobiol. 2018;55(9):7153–7163.
  • Moroni F, Cozzi A, Chiarugi A, et al. Long-lasting neuroprotection and neurological improvement in stroke models with new, potent and brain permeable inhibitors of poly(ADP-ribose) polymerase. Br J Pharmacol. 2012;165(5):1487–1500.
  • Lenzsér G, Kis B, Snipes JA, et al. Contribution of poly(ADP-ribose) polymerase to postischemic blood–brain barrier damage in rats. J Cereb Blood Flow Metab. 2007;27(7):1318–1326.
  • Crome O, Doeppner TR, Schwarting S, et al. Enhanced poly(ADP-ribose) polymerase-1 activation contributes to recombinant tissue plasminogen activator-induced aggravation of ischemic brain injury in vivo. J Neurosci Res. 2007;85(8):1734–1743.
  • Teng F, Beray-Berthat V, Coqueran B, et al. Prevention of rt-PA induced blood–brain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in mice. Exp Neurol. 2013;248:416–428.
  • Haddad M, Beray-Berthat V, Coqueran B, et al. Combined therapy with PJ34, a poly(ADP-ribose)polymerase inhibitor, reduces tissue plasminogen activator-induced hemorrhagic transformations in cerebral ischemia in mice. Fundam Clin Pharmacol. 2013;27(4):393–401.
  • Haddad M, Beray-Berthat V, Coqueran B, et al. Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice. Eur J Pharmacol. 2008;588(1):52–57.
  • El Amki M, Lerouet D, Garraud M, et al. Improved reperfusion and vasculoprotection by the poly(ADP-ribose) polymerase inhibitor PJ34 after stroke and thrombolysis in mice. Mol Neurobiol. 2018. DOI:10.1007/s12035-018-1063-3
  • Sarchielli P, Galli F, Floridi A, et al. Relevance of protein nitration in brain injury: a key pathophysiological mechanism in neurodegenerative, autoimmune, or inflammatory CNS diseases and stroke. Amino Acids. 2003;25(3–4):427–436.
  • Rao R. Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front Biosci. 2008;13:7210–7226.
  • Salter MW, Kalia LV. Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci. 2004;5(4):317–328.
  • Kmiecik TE, Shalloway D. Activation and suppression of pp60c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell. 1987;49(1):65–73.
  • Xu W, Doshi A, Lei M, et al. Crystal structures of c-Src reveal features of its autoinhibitory mechanism. Mol Cell. 1999;3(5):629–638.
  • Engen JR, Wales TE, Hochrein JM, et al. Structure and dynamic regulation of Src-family kinases. Cell Mol Life Sci. 2008;65(19):3058–3073.
  • Brown MT, Cooper JA. Regulation, substrates and functions of src. Biochim Biophys Acta. 1996;1287(2–3):121–149.
  • Kuo WL, Chung KC, Rosner MR. Differentiation of central nervous system neuronal cells by fibroblast-derived growth factor requires at least two signaling pathways: roles for Ras and Src. Mol Cell Biol. 1997;17(8):4633–4643.
  • Hoffman-Kim D, Kerner JA, Chen A, et al. pp60(c-src) is a negative regulator of laminin-1-mediated neurite outgrowth in chick sensory neurons. Mol Cell Neurosci. 2002;21(1):81–93.
  • MacFarlane SN, Sontheimer H. Modulation of Kv1.5 currents by Src tyrosine phosphorylation: potential role in the differentiation of astrocytes. J Neurosci. 2000;20(14):5245–5253.
  • Tsuda S, Ohtsuru A, Yamashita S, et al. Role of c-Fyn in FGF-2-mediated tube-like structure formation by murine brain capillary endothelial cells. Biochem Biophys Res Commun. 2002;290(4):1354–1360.
  • Liu DZ, Ander BP, Xu H, et al. Blood–brain barrier breakdown and repair by Src after thrombin-induced injury. Ann Neurol. 2010;67(4):526–533.
  • Zan L, Wu H, Jiang J, et al. Temporal profile of Src, SSeCKS, and angiogenic factors after focal cerebral ischemia: correlations with angiogenesis and cerebral edema. Neurochem Int. 2011;58(8):872–879.
  • Bai Y, Xu G, Xu M, et al. Inhibition of Src phosphorylation reduces damage to the blood–brain barrier following transient focal cerebral ischemia in rats. Int J Mol Med. 2014;34(6):1473–1482.
  • Paul R, Zhang ZG, Eliceiri BP, et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med. 2001;7(2):222–227.
  • Takenaga Y, Takagi N, Murotomi K, et al. Inhibition of Src activity decreases tyrosine phosphorylation of occludin in brain capillaries and attenuates increase in permeability of the blood–brain barrier after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2009;29(6):1099–1108.
  • Lennmyr F, Ericsson A, Gerwins P, et al. Src family kinase-inhibitor PP2 reduces focal ischemic brain injury. Acta Neurol Scand. 2004;110(3):175–179.
  • Zan L, Zhang X, Xi Y, et al. Src regulates angiogenic factors and vascular permeability after focal cerebral ischemia–reperfusion. Neuroscience. 2014;262:118–128.
  • Eliceiri BP, Paul R, Schwartzberg PL, et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell. 1999;4(6):915–924.
  • Mukhopadhyay D, Tsiokas L, Zhou XM, et al. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature. 1995;375(6532):577–581.
  • Zhang ZG, Zhang L, Tsang W, et al. Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia. J Cereb Blood Flow Metab. 2002;22(4):379–392.
  • Yu XM, Askalan R, Keil GJ, 2nd, et al. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science. 1997;275(5300):674–678.
  • Yang M, Leonard JP. Identification of mouse NMDA receptor subunit NR2A C-terminal tyrosine sites phosphorylated by coexpression with v-Src. J Neurochem. 2001;77(2):580–588.
  • Zheng F, Gingrich MB, Traynelis SF, et al. Tyrosine kinase potentiates NMDA receptor currents by reducing tonic zinc inhibition. Nat Neurosci. 1998;1(3):185–191.
  • Takagi N, Shinno K, Teves L, et al. Transient ischemia differentially increases tyrosine phosphorylation of NMDA receptor subunits 2A and 2B. J Neurochem. 1997;69(3):1060–1065.
  • Cheung HH, Teves L, Wallace MC, et al. Inhibition of protein kinase C reduces ischemia-induced tyrosine phosphorylation of the N-methyl-d-aspartate receptor. J Neurochem. 2003;86(6):1441–1449.
  • Liu D, Zhang X, Hu B, et al. Src family kinases in brain edema after acute brain injury. Acta Neurochir Suppl. 2016;121:185–190.
  • Riek-Burchardt M, Striggow F, Henrich-Noack P, et al. Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors. Neurosci Lett. 2002;329(2):181–184.
  • Karabiyikoglu M, Hua Y, Keep RF, et al. Intracerebral hirudin injection attenuates ischemic damage and neurologic deficits without altering local cerebral blood flow. J Cereb Blood Flow Metab. 2004;24(2):159–166.
  • Liu DZ, Cheng XY, Ander BP, et al. Src kinase inhibition decreases thrombin-induced injury and cell cycle re-entry in striatal neurons. Neurobiol Dis. 2008;30(2):201–211.
  • Huang W, Liu Y, Li L, et al. HMGB1 increases permeability of the endothelial cell monolayer via RAGE and Src family tyrosine kinase pathways. Inflammation. 2012;35(1):350–362.
  • Balosso S, Liu J, Bianchi ME, et al. Disulfide-containing high mobility group box-1 promotes N-methyl-D-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal. 2014;21(12):1726–1740.
  • Corcoran A, Cotter TG. Redox regulation of protein kinases. FEBS J. 2013;280(9):1944–1965.
  • Giannoni E, Taddei ML, Chiarugi P. Src redox regulation: again in the front line. Free Radic Biol Med. 2010;49(4):516–527.
  • Giannoni E, Buricchi F, Raugei G, et al. Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol Cell Biol. 2005;25(15):6391–6403.
  • Oo ML, Senga T, Thant AA, et al. Cysteine residues in the C-terminal lobe of Src: their role in the suppression of the Src kinase. Oncogene. 2003;22(9):1411–1417.
  • Akhand AA, Pu M, Senga T, et al. Nitric oxide controls src kinase activity through a sulfhydryl group modification-mediated Tyr-527-independent and Tyr-416-linked mechanism. J Biol Chem. 1999;274(36):25821–25826.
  • Rosado JA, Redondo PC, Salido GM, et al. Hydrogen peroxide generation induces pp60src activation in human platelets: evidence for the involvement of this pathway in store-mediated calcium entry. J Biol Chem. 2004;279(3):1665–1675.
  • Reiter CD, Teng RJ, Beckman JS. Superoxide reacts with nitric oxide to nitrate tyrosine at physiological pH via peroxynitrite. J Biol Chem. 2000;275(42):32460–32466.
  • MacMillan-Crow LA, Greendorfer JS, Vickers SM, et al. Tyrosine nitration of C-src tyrosine kinase in human pancreatic ductal adenocarcinoma. Arch Biochem Biophys. 2000;377(2):350–356.
  • Minetti M, Mallozzi C, Di Stasi AM. Peroxynitrite activates kinases of the src family and upregulates tyrosine phosphorylation signaling. Free Radic Biol Med. 2002;33(6):744–754.
  • Mallozzi C, Di Stasi AM, Minetti M. Activation of src tyrosine kinases by peroxynitrite. FEBS Lett. 1999;456(1):201–206.
  • Di Stasi AM, Mallozzi C, Macchia G, et al. Peroxynitrite induces tryosine nitration and modulates tyrosine phosphorylation of synaptic proteins. J Neurochem. 1999;73(2):727–735.
  • Mallozzi C, Di Stasi MA, Minetti M. Peroxynitrite-dependent activation of src tyrosine kinases lyn and hck in erythrocytes is under mechanistically different pathways of redox control. Free Radic Biol Med. 2001;30(10):1108–1117.
  • Serafini M, Mallozzi C, Di Stasi AM, et al. Peroxynitrite-dependent upregulation of SRC kinases in red blood cells: strategies to study the activation mechanisms. Methods Enzymol. 2005;396:215–229.
  • Takakura K, Beckman JS, MacMillan-Crow LA, et al. Rapid and irreversible inactivation of protein tyrosine phosphatases PTP1B, CD45, and LAR by peroxynitrite. Arch Biochem Biophys. 1999;369(2):197–207.
  • Mallozzi C, Di Stasi AM, Minetti M. Peroxynitrite modulates tyrosine-dependent signal transduction pathway of human erythrocyte band 3. FASEB J. 1997;11(14):1281–1290.
  • Mallozzi C, Di Stasi AM, Minetti M. Nitrotyrosine mimics phosphotyrosine binding to the SH2 domain of the src family tyrosine kinase lyn. FEBS Lett. 2001;503(2–3):189–195.
  • Haskew RE, Mongin AA, Kimelberg HK. Peroxynitrite enhances astrocytic volume-sensitive excitatory amino acid release via a src tyrosine kinase-dependent mechanism. J Neurochem. 2002;82(4):903–912.
  • Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-I and ROCK-II, Two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996;392(2):189–193.
  • Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4(6):446–456.
  • Amano M, Fukata Y, Kaibuchi K. Regulation and functions of Rho-associated kinase. Exp Cell Res. 2000;261(1):44–51.
  • van Hinsbergh VW, van Nieuw Amerongen GP. Intracellular signalling involved in modulating human endothelial barrier function. J Anat. 2002;200(6):549–560.
  • Nunes KP, Rigsby CS, Webb RC. RhoA/Rho-kinase and vascular diseases: what is the link? Cell Mol Life Sci. 2010;67(22):3823–3836.
  • Du L, Kim JJ, Shen J, et al. Crosstalk between inflammation and ROCK/MLCK signaling pathways in gastrointestinal disorders with intestinal hyperpermeability. Gastroenterol Res Pract. 2016;2016:7374197.
  • Wojciak-Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol. 2002;39(4–5):187–199.
  • Takemoto M, Sun J, Hiroki J, et al. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002;106(1):57–62.
  • Sun H, Breslin JW, Zhu J, et al. Rho and ROCK signaling in VEGF-induced microvascular endothelial hyperpermeability. Microcirculation. 2006;13(3):237–247.
  • Yamashita K, Kotani Y, Nakajima Y, et al. Fasudil, a Rho kinase (ROCK) inhibitor, protects against ischemic neuronal damage in vitro and in vivo by acting directly on neurons. Brain Res. 2007;1154:215–224.
  • Rikitake Y, Kim HH, Huang Z, et al. Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke. 2005;36(10):2251–2257.
  • Li Q, Huang XJ, He W, et al. Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats. Cell Mol Neurobiol. 2009;29(2):169–180.
  • Gibson CL, Srivastava K, Sprigg N, et al. Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. J Neurochem. 2014;129(5):816–826.
  • Wei XE, Zhang FY, Wang K, et al. Fasudil hydrochloride protects neurons in rat hippocampal CA1 region through inhibiting GluR6-MLK3-JNKs signal pathway. Cell Biochem Biophys. 2014;70(1):415–421.
  • Hitomi A, Satoh S, Ikegaki I, et al. Hemorheological abnormalities in experimental cerebral ischemia and effects of protein kinase inhibitor on blood fluidity. Life Sci. 2000;67(16):1929–1939.
  • Satoh S-I, Utsunomiya T, Tsurui K, et al. Pharmacological profile of hydroxy fasudil as a selective Rho kinase inhibitor on ischemic brain damage. Life Sci. 2001;69(12):1441–1453.
  • Niggli V. Rho-kinase in human neutrophils: a role in signalling for myosin light chain phosphorylation and cell migration. FEBS Lett. 1999;445(1):69–72.
  • Satoh S, Kobayashi T, Hitomi A, et al. Inhibition of neutrophil migration by a protein kinase inhibitor for the treatment of ischemic brain infarction. Jpn J Pharmacol. 1999;80(1):41–48.
  • Shibuya M, Hirai S, Seto M, et al. Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial. J Neurol Sci. 2005;238(1–2):31–39.
  • Niego B, Freeman R, Puschmann TB, et al. T-PA-specific modulation of a human blood–brain barrier model involves plasmin-mediated activation of the Rho kinase pathway in astrocytes. Blood. 2012;119(20):4752–4761.
  • Fukuta T, Yanagida Y, Asai T, et al. Co-administration of liposomal fasudil and tissue plasminogen activator ameliorated ischemic brain damage in occlusion model rats prepared by photochemically induced thrombosis. Biochem Biophys Res Commun. 2018;495(1):873–877.
  • Fukuta T, Asai T, Yanagida Y, et al. Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke. FASEB J. 2017;31(5):1879–1890.
  • Perez-Vizcaino F, Cogolludo A, Moreno L. Reactive oxygen species signaling in pulmonary vascular smooth muscle. Respir Physiol Neurobiol. 2010;174(3):212–220.
  • Bailey SR, Mitra S, Flavahan S, et al. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol. 2005;289(1):H243–H250.
  • Meng Y, Li T, Zhou GS, et al. The angiotensin-converting enzyme 2/angiotensin (1–7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway. Antioxid Redox Signal. 2015;22(3):241–258.
  • Cinel I, Ark M, Dellinger P, et al. Involvement of Rho kinase (ROCK) in sepsis-induced acute lung injury. J Thorac Dis. 2012;4(1):30–39.
  • Jernigan NL, Walker BR, Resta TC. Reactive oxygen species mediate RhoA/Rho kinase-induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia. Am J Physiol Lung Cell Mol Physiol. 2008;295(3):L515–L529.
  • de Souza P, Guarido KL, Scheschowitsch K, et al. Impaired vascular function in sepsis-surviving rats mediated by oxidative stress and Rho-kinase pathway. Redox Biol. 2016;10:140–147.
  • Sun Z, Wu X, Li W, et al. RhoA/rock signaling mediates peroxynitrite-induced functional impairment of Rat coronary vessels. BMC Cardiovasc Disord. 2016;16(1):193.
  • Chandra S, Romero MJ, Shatanawi A, et al. Oxidative species increase arginase activity in endothelial cells through the RhoA/Rho kinase pathway. Br J Pharmacol. 2012;165(2):506–519.
  • Soliman H, Craig GP, Nagareddy P, et al. Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats. Cardiovasc Res. 2008;79(2):322–330.
  • Cohen P, Goedert M. GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov. 2004;3(6):479–487.
  • Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol. 2001;2(10):769–776.
  • Leroy K, Brion JP. Developmental expression and localization of glycogen synthase kinase-3beta in rat brain. J Chem Neuroanat. 1999;16(4):279–293.
  • Yao HB, Shaw PC, Wong CC, et al. Expression of glycogen synthase kinase-3 isoforms in mouse tissues and their transcription in the brain. J Chem Neuroanat. 2002;23(4):291–297.
  • Hughes K, Nikolakaki E, Plyte SE, et al. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993;12(2):803–808.
  • Nonaka S, Chuang DM. Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats. NeuroReport. 1998;9(9):2081–2084.
  • Wang JM, Hayashi T, Zhang WR, et al. Reduction of ischemic brain injury by topical application of insulin-like growth factor-I after transient middle cerebral artery occlusion in rats. Brain Res. 2000;859(2):381–385.
  • Collino M, Thiemermann C, Mastrocola R, et al.Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. Shock. 2008;30(3):299–307.
  • Venna VR, Benashski SE, Chauhan A, et al. Inhibition of glycogen synthase kinase-3beta enhances cognitive recovery after stroke: the role of TAK1. Learn Mem. 2015;22(7):336–343.
  • Kelly S, Zhao H, Hua Sun G, et al. Glycogen synthase kinase 3β inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia. Exp Neurol. 2004;188(2):378–386.
  • Zhou X, Zhou J, Li X, et al. GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury. Biochem Biophys Res Commun. 2011;411(2):271–275.
  • Schäfer M, Goodenough S, Moosmann B, et al. Inhibition of glycogen synthase kinase 3β is involved in the resistance to oxidative stress in neuronal HT22 cells. Brain Res. 2004;1005(1–2):84–89.
  • Hanumanthappa P, Densi A, Krishnamurthy RG. Glycogen synthase kinase-β3 in ischemic neuronal death. Curr Neurovasc Res. 2014;11(3):271–278.
  • Pang T, Wang YJ, Gao YX, et al.A novel GSK-3beta inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway. Acta Pharmacol Sin. 2016;37(6):741–752.
  • Valerio A, Bertolotti P, Delbarba A, et al. Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production. J Neurochem. 2011;116(6):1148–1159.
  • Koh SH, Yoo AR, Chang DI, et al. Inhibition of GSK-3 reduces infarct volume and improves neurobehavioral functions. Biochem Biophys Res Commun. 2008;371(4):894–899.
  • Huang S, Wang H, Turlova E, et al. GSK-3beta inhibitor TDZD-8 reduces neonatal hypoxic-ischemic brain injury in mice. CNS Neurosci Ther. 2017;23(5):405–415.
  • Li Y, Zhu J, Liu Y, et al. Glycogen synthase kinase 3beta influences injury following cerebral ischemia/reperfusion in rats. Int J Biol Sci. 2016;12(5):518–531.
  • D’Angelo B, Ek CJ, Sun Y, et al. GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling. Neuropharmacology. 2016;101(Suppl c):13–23.
  • Xiao H, Deng M, Yang B, et al. Role of glycogen synthase kinase 3 in ischemia-induced blood–brain barrier disruption in aged female rats. J Neurochem. 2017;142(2):194–203.
  • Ramirez SH, Fan S, Dykstra H, et al. Inhibition of glycogen synthase kinase 3beta promotes tight junction stability in brain endothelial cells by half-life extension of occludin and claudin-5. PLoS One. 2013;8(2):e55972.
  • Perez-Alvarez MJ, Mateos L, Alonso A, et al. Estradiol and progesterone administration after pMCAO stimulates the neurological recovery and reduces the detrimental effect of ischemia mainly in hippocampus. Mol Neurobiol. 2015;52(3):1690–1703.
  • Li M, Zhang Z, Sun W, et al. 17β-estradiol attenuates breakdown of blood–brain barrier and hemorrhagic transformation induced by tissue plasminogen activator in cerebral ischemia. Neurobiol Dis. 2011;44(3):277–283.
  • Han F, Ali Raie A, Shioda N, et al. Accumulation of beta-amyloid in the brain microvessels accompanies increased hyperphosphorylated tau proteins following microsphere embolism in aged rats. Neuroscience. 2008;153(2):414–427.
  • Yin J, Liu YH, Xu YF, et al. Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain. J Pineal Res. 2006;41(2):124–129.
  • Zhang YJ, Xu YF, Liu YH, et al. Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. FASEB J. 2006;20(9):1431–1442.
  • Hellberg CB, Boggs SE, Lapetina EG. Phosphatidylinositol 3-kinase is a target for protein tyrosine nitration. Biochem Biophys Res Commun. 1998;252(2):313–317.
  • Won JS, Annamalai B, Choi S, et al. S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion. Brain Res. 2015;1624:359–369.
  • Yang X, Chu H, Tang Y, et al. The role of connexin43 in hemorrhagic transformation after thrombolysis in vivo and in vitro. Neuroscience. 2016;329:54–65.
  • Song H, Cheng Y, Bi G, et al. Release of matrix Metalloproteinases-2 and 9 by S-Nitrosylated Caveolin-1 contributes to degradation of extracellular matrix in tPA-treated hypoxic endothelial cells. PLoS One. 2016;11(2):e0149269.
  • Sang H, Qiu Z, Cai J, et al.Early increased bradykinin 1 receptor contributes to hemorrhagic transformation after ischemic stroke in Type 1 diabetic rats. Transl Stroke Res. 2017;8(6):597–611.
  • Kim JM, Lee JC, Chang N, et al. S-allyl-L-cysteine attenuates cerebral ischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellular signal-regulated kinase. Free Radic Res. 2006;40(8):827–835.
  • Mahmood Q, Wang GF, Wu G, et al. Salvianolic acid A inhibits calpain activation and eNOS uncoupling during focal cerebral ischemia in mice. Phytomedicine. 2017;25:8–14.
  • Li S, Lin W, Tchantchou F, et al. Protein kinase C mediates peroxynitrite toxicity to oligodendrocytes. Mol Cell Neurosci. 2011;48(1):62–71.
  • Tan Z, Lucke-Wold BP, Logsdon AF, et al.Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats. Eur J Pharmacol 2015;764:404–412.
  • Rao RK, Basuroy S, Rao VU, et al. Tyrosine phosphorylation and dissociation of occludin–ZO-1 and E-cadherin–β-catenin complexes from the cytoskeleton by oxidative stress. Biochem J. 2002;368(2):471–481.
  • Feng J, Chen X, Shen J. Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke. Expert Opin Ther Targets. 2017;21(3):305–317.
  • Mathiisen TM, Lehre KP, Danbolt NC, et al. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia. 2010;58(9):1094–1103.
  • Abbott NJ. Astrocyte-endothelial interactions and blood–brain barrier permeability. J Anat. 2002;200(6):629–638.
  • Abbott NJ, Rönnbäck L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.
  • Liu Z, Chopp M. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol. 2016;144:103–120.
  • Li YN, Pan R, Qin XJ, et al. Ischemic neurons activate astrocytes to disrupt endothelial barrier via increasing VEGF expression. J Neurochem. 2014;129(1):120–129.
  • Becerra-Calixto A, Cardona-Gómez GP. The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci. 2017;10:88.
  • Yamashita T, Kamiya T, Deguchi K, et al. Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. J Cereb Blood Flow Metab. 2009;29(4):715–725.
  • Choi IY, Kim WK. Etoposide reduces peroxynitrite-induced cytotoxicity via direct scavenging effect. Exp Neurobiol. 2010;19(2):90–96.
  • Yoo oK, Choi JW, Choi MS, et al. Mitogen-activated protein kinases (MAPKs) mediate SIN-1/glucose deprivation-induced death in rat primary astrocytes. Arch Pharm Res. 2005;28(8):942–947.
  • Choi JW, Yoo BK, Ryu MK, et al. Adenosine and purine nucleosides prevent the disruption of mitochondrial transmembrane potential by peroxynitrite in rat primary astrocytes. Arch Pharm Res. 2005;28(7):810–815.
  • Muyderman H, Nilsson M, Sims NR. Highly selective and prolonged depletion of mitochondrial glutathione in astrocytes markedly increases sensitivity to peroxynitrite. J Neurosci. 2004;24(37):8019–8028.
  • Kimelberg HK. Increased release of excitatory amino acids by the actions of ATP and peroxynitrite on volume-regulated anion channels (VRACs) in astrocytes. Neurochem Int. 2004;45(4):511–519.
  • Ju C, Oh YJ, Han BH, et al. Intracellular pH-dependent peroxynitrite-evoked synergistic death of glucose-deprived astrocytes. Free Radic Biol Med. 2004;37(8):1160–1169.
  • Acquaviva R, Campisi A, Murabito P, et al. Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism. Anesthesiology. 2004;101(6):1363–1371.
  • Choi JJ, Oh YK, Kim HS, et al. Mimosine prevents the death of glucose-deprived immunostimulated astrocytes by scavenging peroxynitrite. Glia. 2002;39(1):37–46.
  • Choi JJ, Kong MY, Lee SJ, et al. Ciclopirox prevents peroxynitrite toxicity in astrocytes by maintaining their mitochondrial function: a novel mechanism for cytoprotection by ciclopirox. Neuropharmacology. 2002;43(3):408–417.
  • Choi IY, Lee SJ, Nam W, et al.Augmented death in immunostimulated astrocytes deprived of glucose: inhibition by an iron porphyrin FeTMPyP. J Neuroimmunol. 2001;112(1–2):55–62.
  • Choi IY, Lee SJ, Ju C, et al. Protection by a manganese porphyrin of endogenous peroxynitrite-induced death of glial cells via inhibition of mitochondrial transmembrane potential decrease. Glia. 2000;31(2):155–164.
  • Wu J, Li J, Hu H, et al. Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain. Cell Mol Neurobiol. 2012;32(7):1187–1197.
  • Waldow T, Witt W, Matschke K. Inhibition of glycogen synthase kinase-3beta prevents activation of focal adhesion kinase after ischemia/reperfusion of the rat lung. Clin Hemorheol Microcirc. 2010;46(2–3):169–181.
  • Fu S, Gu Y, Jiang JQ, et al. Calycosin-7-O-β-d-glucoside regulates nitric oxide/caveolin-1/matrix metalloproteinases pathway and protects blood–brain barrier integrity in experimental cerebral ischemia–reperfusion injury. J Ethnopharmacol. 2014;155(1):692–701.
  • Ji B, Zhou F, Han L, et al.Sodium tanshinone IIA sulfonate enhances effectiveness rt-PA treatment in acute ischemic stroke patients associated with ameliorating blood–brain barrier damage. Transl Stroke Res. 2017;8(4):334–340.
  • del Zoppo GJ. The neurovascular unit in the setting of stroke. J Intern Med. 2010;267(2):156–171.
  • Wang Y, Li Q, Wang J, et al. Combination of thrombolytic therapy and neuroprotective therapy in acute ischemic stroke: is it important? Eur Rev Med Pharmacol Sci. 2015;19(3):416–422.
  • Whiteley WN, Emberson J, Lees KR, et al. Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet Neurol. 2016;15(9):925–933.
  • Tu XK, Yang WZ, Shi SS, et al. Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation. 2011;34(5):463–470.
  • Li HY, Yuan ZY, Wang YG, et al. Role of baicalin in regulating Toll-like receptor 2/4 after ischemic neuronal injury. Chin Med J. 2012;125(9):1586–1593.
  • Iglesias-Rey R, Rodríguez-Yáñez M, Rodríguez-Castro E, et al.Worse outcome in stroke patients treated with rt-PA without early reperfusion: associated factors. Transl Stroke Res. 2018;9(4):347–355.
  • Fagan SC, Lapchak PA, Liebeskind DS, et al. Recommendations for preclinical research in hemorrhagic transformation. Transl Stroke Res. 2013;4(3):322–327.
  • Fan X, Jiang Y, Yu Z, et al. Annexin A2 plus low-dose tissue plasminogen activator combination attenuates cerebrovascular dysfunction after focal embolic stroke of rats. Transl Stroke Res. 2017;8(6):549–559.
  • Uzdensky AB. Photothrombotic stroke as a model of ischemic stroke. Transl Stroke Res. 2017;9(5):437–451.
  • Lapchak PA, Uteshev VV. Stroke cytoprotection: can repeating history with new expectations really be the path to success in stroke research? Transl Stroke Res. 2017;8(2):104–106.
  • Lim SY, Jang JH, Na HK, et al. 15-deoxy-Delta12,14-prostaglandin J(2) protects against nitrosative PC12 cell death through up-regulation of intracellular glutathione synthesis. J Biol Chem. 2004;279(44):46263–46270.
  • Li MH, Cha YN, Surh YJ. Carbon monoxide protects PC12 cells from peroxynitrite-induced apoptotic death by preventing the depolarization of mitochondrial transmembrane potential. Biochem Biophys Res Commun. 2006;342(3):984–990.
  • Surh YJ, Kundu JK, Li MH, et al. Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Arch Pharm Res. 2009;32(8):1163–1176.
  • Li MH, Jang JH, Na HK, et al. Carbon monoxide produced by heme oxygenase-1 in response to nitrosative stress induces expression of glutamate-cysteine ligase in PC12 cells via activation of phosphatidylinositol 3-kinase and Nrf2 signaling. J Biol Chem. 2007;282(39):28577–28586.
  • Li MH, Cha YN, Surh YJ. Peroxynitrite induces HO-1 expression via PI3K/Akt-dependent activation of NF-E2-related factor 2 in PC12 cells. Free Radic Biol Med. 2006;41(7):1079–1091.
  • Prakash R, Somanath PR, El-Remessy AB, et al. Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes. 2012;61(6):1533–1542.
  • Platt DH, Bartoli M, El-Remessy AB, et al. Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3. Free Radic Biol Med. 2005;39(10):1353–1361.
  • Hayakawa K, Pham LD, Katusic ZS, et al. Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc Natl Acad Sci USA. 2012;109(19):7505–7510.
  • Chen C, Lin X, Wang J, et al. Effect of HMGB1 on the paracrine action of EPC promotes post-ischemic neovascularization in mice. Stem Cells. 2014;32(10):2679–2689.
  • Hayakawa K, Nakano T, Irie K, et al.Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2010;30(4):871–882.
  • Richard SA, Sackey M, Su Z, et al. Pivotal neuroinflammatory and therapeutic role of high mobility group box 1 in ischemic stroke. Biosci Rep. 2017;37(6).
  • Zhao BQ, Wang S, Kim HY, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12(4):441–445.
  • Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 2015;1623:30–38.
  • Zhao BQ, Tejima E, Lo EH. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke. 2007;38(2 Suppl):748–752.
  • Liu DZ, Sharp FR. The dual role of SRC kinases in intracerebral hemorrhage. Acta Neurochir Suppl. 2011;111:77–81.
  • Li W, Ward R, Valenzuela JP, et al. Diabetes worsens functional outcomes in young female rats: comparison of stroke models, tissue plasminogen activator effects, and sexes. Transl Stroke Res. 2017;8(5):429–439.
  • Lapchak PA, Zhang JH. Translational stroke research guideline projections: the 20/20 standards. Transl Stroke Res. 2018;9(1):9–12.
  • Henning EC, Latour LL, Hallenbeck JM, et al. Reperfusion-associated hemorrhagic transformation in SHR rats: evidence of symptomatic parenchymal hematoma. Stroke. 2008;39(12):3405–3410.
  • Ergul A, Elgebaly MM, Middlemore ML, et al. Increased hemorrhagic transformation and altered infarct size and localization after experimental stroke in a rat model type 2 diabetes. BMC Neurol. 2007;7:33.
  • Zhang Z, Yan J, Shi H. Hyperglycemia as a risk factor of ischemic stroke. J Drug Metab Toxicol. 2013;4(4):153.
  • Kim D, Choi I-Y, Jang H, et al. HMGB1 suppression confers neuroprotection against stroke in diabetic rats. Transl Neurosci. 2013;4(4):477–483.
  • Justicia C, Salas-Perdomo A, Pérez-de-Puig I, et al. Uric acid is protective after cerebral ischemia/reperfusion in hyperglycemic mice. Transl Stroke Res. 2017;8(3):294–305.

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