Journal of Neurology

, 258:1885 | Cite as

No evidence for an association between genetic variation at the SERPINI1 locus and ischemic stroke

  • A. Tjärnlund-Wolf
  • S. Olsson
  • K. Jood
  • C. Blomstrand
  • C. JernEmail author
Letter to the Editors

Dear Sirs,

Neuroserpin, primarily expressed by neurons, is an important inhibitor of tissue-type plasminogen activator (t-PA). t-PA has a multifaceted role in the brain and is involved in several physiologic and pathologic processes. Its beneficial role on the vascular side is attributed to its thrombolytic function. Moreover, recombinant t-PA is the only FDA-approved pharmacological treatment of acute ischemic stroke (IS) [1]. In the brain there are several cell-types that express t-PA besides the cerebrovascular endothelial cells, e.g. neurons, microglia and astrocytes [2]. Under physiological conditions t-PA is involved in synaptic plasticity and memory-related processes [3, 4]. However, during pathological conditions, such as in the acute phase of IS, excess release of t-PA may trigger proteolytic cascades, subsequently leading to excitotoxicity and neurodegeneration [5, 6]. In this context, t-PA has been associated with increased stroke volume [7] and increased cerebrovascular...


Ischemic Stroke Minor Allele Frequency Increase Stroke Volume Brain Barrier Permeability Reduce Infarct Volume 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The present study was supported by the Swedish Research Council (K2011-65X-14605-09-6), the Swedish state (ALFBGB-148861), the Swedish Heart and Lung Foundation (20100256), the Yngve Land Foundation for Neurological Research, the Göteborg Foundation for Neurological Research, the Swedish Brain Foundation, and the John and Brit Wennerström, Rune and Ulla Amlöv, Edit Jacobson, Per-Olof Ahl, Tore Nilsson, and Emelle Foundations. Genotyping was performed by the SNP&SEQ Technology Platform in Uppsala, which is supported by Uppsala University, Uppsala University Hospital, Science for Life Laboratory - Uppsala and the Swedish Research Council (Contracts 80576801 and 70374401).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    (1995) Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 333:1581–1587Google Scholar
  2. 2.
    Teesalu T, Kulla A, Simisker A, Siren V, Lawrence DA, Asser T, Vaheri A (2004) Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system. Thromb Haemost 92:358–368PubMedGoogle Scholar
  3. 3.
    Calabresi P, Napolitano M, Centonze D, Marfia GA, Gubellini P, Teule MA, Berretta N, Bernardi G, Frati L, Tolu M, Gulino A (2000) Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory. Eur J Neurosci 12:1002–1012PubMedCrossRefGoogle Scholar
  4. 4.
    Samson AL, Medcalf RL (2006) Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 50:673–678PubMedCrossRefGoogle Scholar
  5. 5.
    Tsirka SE, Gualandris A, Amaral DG, Strickland S (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377:340–344PubMedCrossRefGoogle Scholar
  6. 6.
    Benchenane K, Lopez-Atalaya JP, Fernandez-Monreal M, Touzani O, Vivien D (2004) Equivocal roles of tissue-type plasminogen activator in stroke-induced injury. Trends Neurosci 27:155–160PubMedCrossRefGoogle Scholar
  7. 7.
    Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA (1998) Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 4:228–231PubMedCrossRefGoogle Scholar
  8. 8.
    Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA (2003) Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 112:1533–1540PubMedGoogle Scholar
  9. 9.
    Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, Gao Y, Pietras K, Mann K, Yepes M, Strickland DK, Betsholtz C, Eriksson U, Lawrence DA (2008) Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 14:731–737PubMedCrossRefGoogle Scholar
  10. 10.
    Polavarapu R, Gongora MC, Yi H, Ranganthan S, Lawrence DA, Strickland D, Yepes M (2007) Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit. Blood 109:3270–3278PubMedCrossRefGoogle Scholar
  11. 11.
    Yepes M, Sandkvist M, Wong MK, Coleman TA, Smith E, Cohan SL, Lawrence DA (2000) Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96:569–576PubMedGoogle Scholar
  12. 12.
    Cinelli P, Madani R, Tsuzuki N, Vallet P, Arras M, Zhao CN, Osterwalder T, Rulicke T, Sonderegger P (2001) Neuroserpin a neuroprotective factor in focal ischemic stroke. Mol Cell Neurosci 18:443–457PubMedCrossRefGoogle Scholar
  13. 13.
    Cole JW, Naj AC, O’Connell JR, Stine OC, Sorkin JD, Wozniak MA, Stern BJ, Yepes M, Lawrence DA, Reinhart LJ, Strickland DK, Mitchell BD, Kittner SJ (2007) Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study. BMC Neurol 7:37PubMedCrossRefGoogle Scholar
  14. 14.
    Jood K, Ladenvall C, Rosengren A, Blomstrand C, Jern C (2005) Family history in ischemic stroke before 70 years of age: the Sahlgrenska Academy Study on Ischemic Stroke. Stroke 36:1383–1387PubMedCrossRefGoogle Scholar
  15. 15.
    Olsson S, Jood K, Blomstrand C, Jern C (2010) Genetic variation on chromosome 9p21 shows association with the ischaemic stroke subtype large-vessel disease in a Swedish sample aged ≤70. Eur J Neurol 18:365–367CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • A. Tjärnlund-Wolf
    • 1
  • S. Olsson
    • 1
  • K. Jood
    • 1
  • C. Blomstrand
    • 1
  • C. Jern
    • 1
    Email author
  1. 1.Institute of Neuroscience and Physiology, Section for Clinical Neuroscience and RehabilitationThe Sahlgrenska Academy at University of GothenburgGothenburgSweden

Personalised recommendations