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Thromb Haemost 2011; 105(03): 421-429
DOI: 10.1160/TH10-09-0621
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

The natural tissue plasminogen activator inhibitor neuroserpin and acute ischaemic stroke outcome

Raquel Rodríguez-González   *
1   Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
,
Mónica Millán   *
2   Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain
,
Tomás Sobrino
1   Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
,
Elena Miranda
3   University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
,
David Brea
1   Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
,
Natalia Pérez de la Ossa
2   Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain
,
Miguel Blanco
1   Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
,
Juan Pérez
4   Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Facultad de Ciencias, Málaga, Spain
,
Laura Dorado
2   Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain
,
Mar Castellanos
5   Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain
,
David A. Lomas
3   University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
,
Maria A. Moro
6   Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
,
Antoni Dávalos
2   Department of Neurosciences, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain
,
José Castillo
1   Clinical Neuroscience Research Laboratory, Department of Neurology, Hospital Clínico Universitario, Universidad de Santiago de Compostela, Santiago de Compostela, Spain
› Author Affiliations
Financial support: This project has been partially supported by grants from the Spanish Ministry of Science and Innovation (CIT-090100–2007–42) and (PI081472); Xunta de Galicia: Consellería de Innovación, Industria e Comercio (PGIDIT06PXIB918316PR), and Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III) RETICS RENEVAS: (RD06/0026). R. Rodríguez-González and D. Brea are recipients of fellowships from Instituto de Salud Carlos III of the Spanish Ministry of Science and Innovation (Ayudas predoctorales de formación en investigación).
Further Information

Publication History

Received: 29 September 2010

Accepted after major revision: 25 November 2010

Publication Date:
27 November 2017 (online)

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Summary

Neuroserpin is a brain-derived natural inhibitor of tissue plasminogen activator (tPA) that has shown neuroprotective effects in animal models of brain ischaemia. Our aim was to investigate the association of neuroserpin levels in blood with functional outcome in patients with acute ischaemic stroke. Due to the potential effect of tPA treatment interfering on neuroserpin levels, we studied two different cohorts: 129 patients not treated with tPA and 80 patients treated with intravenous tPA within 3 hours (h) from symptoms onset. Neuroserpin levels were measured by ELISA. Good functional outcome at three months was defined as Rankin scale score ≤2. In the two cohorts, serum neuroserpin levels on admission were significantly higher than at 24 h, 72 h and in healthy subjects. In non tPA-treated patients, neuroserpin levels decrease at 24 h, but not levels at baseline, were associated with good outcome (for each quartile decrease, adjusted odds ratio [OR] 15.0; 95% confidence interval [CI], 3.5 to 66). In the tPA-treated cohort, high neuroserpin levels before tPA bolus had the stronger effect on favourable outcome (for each quartile, OR 13.5; 95%CI, 3.9 to 47). Furthermore, for each quartile in neuroserpin levels before tPA bolus there was a 80% (95%CI, 48 to 92) reduction in the probability of subsequent parenchymal haematoma. In summary, high serum neuroserpin levels before intravenous tPA and neuroserpin levels decrease at 24 h after ischaemic stroke, independently of tPA treatment, are associated with good functional outcome. These findings support the concept that neuroserpin might play an important role during cerebral ischaemia.

Keywords

Neuroserpin - outcome - stroke - tissue plasminogen activator

* R. Rodríguez- González and M. Millán contributed equally to this work.


 

  • References

  • 1 Hastings GA, Coleman TA, Haudenschild CC. et al. Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival. J Biol Chem 1997; 272: 33062-33067.
    CrossrefPubMedSearch in Google Scholar
  • 2 Hacke W, Donnan G, Fieschi C. et al. ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768-774.
    CrossrefPubMedSearch in Google Scholar
  • 3 Hacke W, Kaste M, Bluhmki E. et al. ECASS Investigators.. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317-1329.
    CrossrefPubMedSearch in Google Scholar
  • 4 Wahlgren N, Ahmed N, Davalos A. et al. SITS investigators.. Thrombolysis with alteplase 3–4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008; 372: 1303-1309.
    CrossrefPubMedSearch in Google Scholar
  • 5 Kaur J, Zhao Z, Klein GM. et al. The neurotoxicity of tissue plasminogen activator?. J Cereb Blood Flow Metab 2004; 24: 945-963.
    CrossrefPubMedSearch in Google Scholar
  • 6 Wang YF, Tsirka SE, Strickland S. et al. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4: 228-231.
    CrossrefPubMedSearch in Google Scholar
  • 7 Yepes M, Sandkvist M, Wong MK. et al. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 2000; 96: 569-576.
    PubMedSearch in Google Scholar
  • 8 Lebeurrier N, Liot G, Lopez-Atalaya JP. et al. The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo. Mol Cell Neurosci 2005; 30: 552-558.
    CrossrefPubMedSearch in Google Scholar
  • 9 Cinelli P, Madani R, Tsuzuki N. et al. Neuroserpin, a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci 2001; 18: 443-457.
    CrossrefPubMedSearch in Google Scholar
  • 10 Madani R, Kozlov S, Akhmedov A. et al. Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin. Mol Cell Neurosci 2003; 23: 473-494.
    CrossrefPubMedSearch in Google Scholar
  • 11 Zhang Z, Zhang L, Yepes M. et al. Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke. Circulation 2002; 106: 740-745.
    CrossrefPubMedSearch in Google Scholar
  • 12 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee.. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457-507.
    CrossrefPubMedSearch in Google Scholar
  • 13 Adams Jr. HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
    CrossrefPubMedSearch in Google Scholar
  • 14 Brott T, Adams Jr HP, Olinger CP. et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20: 864-870.
    CrossrefPubMedSearch in Google Scholar
  • 15 Lyden PD, Hantson L. Assessment scales for the evaluation of stroke patients. J Stroke Cerebrovasc Dis 1998; 7: 113-127.
    CrossrefPubMedSearch in Google Scholar
  • 16 Larrue V, von Kummer RR, Muller A. et al. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke 2001; 32: 438-441.
    CrossrefPubMedSearch in Google Scholar
  • 17 Demchuk AM, Burgin WS, Christou I. et al. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001; 32: 89-93.
    CrossrefPubMedSearch in Google Scholar
  • 18 Miranda E, MacLeod I, Davies MJ. et al. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Hum Mol Genet 2008; 17: 1527-1539.
    CrossrefPubMedSearch in Google Scholar
  • 19 Miranda E, Romisch K, Lomas DA. Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum. J Biol Chem 2004; 279: 28283-28291.
    CrossrefPubMedSearch in Google Scholar
  • 20 Teesalu T, Kulla A, Simisker A. et al. Tissue plasminogen activator and neuroserpin are widely expressed in the central nervous system. Thromb Haemost 2004; 92: 358-368.
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Kennedy SA, van Diepen AC, van der Hurk CM. et al. Expression of the serine pro-tease inhibitor neuroserpin in cells of the human myeloid lineage. Thromb Haemost 2007; 97: 394-399.
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Munuswamy-Ramanujam G, Dai E, Liu L. et al. Neuroserpin, a thrombolytic serine protease inhibitor (serpin), blocks transplant vasculopathy with associated modification of T-helper cell subsets. Thromb Haemost 2010; 103: 545-555.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Barker-Carlson K, Lawrence DA, Schwartz BS. Acyl-enzyme complexes between tissue-type plasminogen activator and neuroserpin are short-lived in vitro. J Biol Chem 2002; 277: 46852-46857.
    CrossrefPubMedSearch in Google Scholar
  • 24 Makarova A, Mikhailenko I, Bugge TH. et al. The low density lipoprotein receptor-related protein modulates protease activity in the brain by mediating the cellular internalization of both neuroserpin and neuroserpin-tissue-type plasminogen activator complexes. J Biol Chem 2003; 278: 50250-50258.
    CrossrefPubMedSearch in Google Scholar
  • 25 Osterwalder T, Cinelli P, Baici A. et al. The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. J Biol Chem 1998; 273: 2312-2321.
    CrossrefPubMedSearch in Google Scholar
  • 26 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: 1533-1540.
    CrossrefPubMedSearch in Google Scholar
  • 27 Benchenane K, Berezowski V, Ali C. et al. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 2005; 111: 2241-2249.
    CrossrefPubMedSearch in Google Scholar
  • 28 Burggraf D, Martens HK, Dichgans M. et al. Matrix metalloproteinase (MMP) induction and inhibition at different doses of recombinant tissue plasminogen activator following experimental stroke. Thromb Haemost 2007; 98: 963-969.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Traynelis SF, Lipton SA. Is tissue plasminogen activator a threat to neurons?. Nat Med 2001; 7: 17-18.
    CrossrefPubMedSearch in Google Scholar
  • 30 Benchenane K, Lopez-Atalaya JP, Fernandez-Monreal M. et al. Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci 2004; 27: 155-160.
    CrossrefPubMedSearch in Google Scholar
  • 31 Zhao G, Reynolds JN, Flavin MP. Temporal profile of tissue plasminogen activator (tPA) and inhibitor expression after transient focal cerebral ischemia. Neurore-port 2003; 14: 1689-1692.
    CrossrefPubMedSearch in Google Scholar
  • 32 Yepes M, Lawrence DA. Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system?. Trends Cardiovasc Med 2004; 14: 173-180.
    CrossrefPubMedSearch in Google Scholar
  • 33 Yepes M, Lawrence DA. New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. Exp Biol Med (Maywood) 2004; 229: 1097-1104.
    CrossrefPubMedSearch in Google Scholar
  • 34 Castellanos M, Leira R, Serena J. et al. Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003; 34: 40-46.
    CrossrefPubMedSearch in Google Scholar
  • 35 Montaner J, Molina CA, Monasterio J. et al. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003; 104: 598-603.
    PubMedSearch in Google Scholar
  • 36 Ning M, Furie KL, Koroshetz WJ. et al. Association between tPA therapy and raised early matrix metalloproteinase-9 in acute stroke. Neurology 2006; 66: 1550-1555.
    CrossrefPubMedSearch in Google Scholar
  • 37 Park KP, Rosell A, Foerch C. et al. Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats. Stroke 2009; 40: 2836-2842.
    CrossrefPubMedSearch in Google Scholar
  • 38 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: 731-737.
    CrossrefPubMedSearch in Google Scholar
  • 39 Yepes M, Lawrence DA. Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost 2004; 91: 457-464.
    Thieme ConnectPubMedSearch in Google Scholar