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Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro.

Publication ,  Journal Article
Sun, H-Y; Szlam, F; Levy, JH; Csete, ME; Tanaka, KA
Published in: Acta Anaesthesiol Scand
March 2009

INTRODUCTION: Serine proteases and their inhibitors play an important role in physiological homeostasis including neuronal activity, hemostasis, and wound healing. Tissue plasminogen activator (tPA) is involved in normal neuronal plasticity and memory formation but can also be neurotoxic. We hypothesized that the serine protease inhibitor aprotinin confers neuronal protection by inhibiting tPA activity. METHODS: Using cultured rat dopaminergic neuroblasts (N27 line), tPA-induced cytotoxicity was quantitated by an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and flow cytometry using propidium iodide DNA staining. The anti-apoptotic effects of aprotinin and other protease inhibitors were also evaluated using these systems. RESULTS: Treatment of cultured neuroblasts with tPA (10-20 microg/ml) caused a dose-dependent decrease in cell viability (71.3+/-2.4 at 10 microg/ml down to 52.7+/-2.5% at 20 microg/m tPA, 24-h treatment), which was potentiated in the absence of serum in the culture medium (59.5+/-6.3% at 10 microg/ml down to 47.9+/-4.7% at 20 microg/ml). Aprotinin was effective in ameliorating cell death when administered 30 min before tPA exposure as shown by increased cell viability (91.8+/-0.6% at tPA at 20 microg/ml), but this protection was significantly reduced when aprotinin was administered after tPA. The efficacy of aprotinin as a neuroprotectant was equivalent or superior to other direct tPA antagonist peptides Glu-Gly-Arg-chlormethylketone (EGRck) and Phe-Pro-Arg-chlormethylketone (FPRck) in this setting. CONCLUSION: These data suggest that one of the mechanisms of neuroprotection afforded by aprotinin may be inhibition of tPA-mediated neurotoxicity.

Duke Scholars

Published In

Acta Anaesthesiol Scand

DOI

EISSN

1399-6576

Publication Date

March 2009

Volume

53

Issue

3

Start / End Page

325 / 331

Location

England

Related Subject Headings

  • Tissue Plasminogen Activator
  • Rats
  • Neurons
  • Flow Cytometry
  • Cytoprotection
  • Cell Line
  • Antifibrinolytic Agents
  • Animals
  • Anesthesiology
  • 3209 Neurosciences
 

Citation

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Sun, H.-Y., Szlam, F., Levy, J. H., Csete, M. E., & Tanaka, K. A. (2009). Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro. Acta Anaesthesiol Scand, 53(3), 325–331. https://doi.org/10.1111/j.1399-6576.2008.01858.x
Sun, H. -. Y., F. Szlam, J. H. Levy, M. E. Csete, and K. A. Tanaka. “Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro.Acta Anaesthesiol Scand 53, no. 3 (March 2009): 325–31. https://doi.org/10.1111/j.1399-6576.2008.01858.x.
Sun H-Y, Szlam F, Levy JH, Csete ME, Tanaka KA. Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro. Acta Anaesthesiol Scand. 2009 Mar;53(3):325–31.
Sun, H. .. Y., et al. “Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro.Acta Anaesthesiol Scand, vol. 53, no. 3, Mar. 2009, pp. 325–31. Pubmed, doi:10.1111/j.1399-6576.2008.01858.x.
Sun H-Y, Szlam F, Levy JH, Csete ME, Tanaka KA. Antifibrinolytic agents reduce tissue plasminogen activator-mediated neuronal toxicity in vitro. Acta Anaesthesiol Scand. 2009 Mar;53(3):325–331.
Journal cover image

Published In

Acta Anaesthesiol Scand

DOI

EISSN

1399-6576

Publication Date

March 2009

Volume

53

Issue

3

Start / End Page

325 / 331

Location

England

Related Subject Headings

  • Tissue Plasminogen Activator
  • Rats
  • Neurons
  • Flow Cytometry
  • Cytoprotection
  • Cell Line
  • Antifibrinolytic Agents
  • Animals
  • Anesthesiology
  • 3209 Neurosciences