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Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons.

Publication ,  Journal Article
García, PS; Ciavatta, VT; Fidler, JA; Woodbury, A; Levy, JH; Tyor, WR
Published in: Neurochem Res
November 2015

Thrombin's role in the nervous system is not well understood. Under conditions of blood-brain barrier compromise (e.g., neurosurgery or stroke), thrombin can result in neuroapoptosis and the formation of glial scars. Despite this, preconditioning with thrombin has been found to be neuroprotective in models of cerebral ischemia and intracerebral hemorrhage. We investigated the effects of physiologically relevant concentrations of thrombin on cortical neurons using two culture-based assays. We examined thrombin's effect on neurites by quantitative analysis of fluorescently labeled neurons. To characterize thrombin's effects on neuron survival, we spectrophotometrically measured changes in enzymatic activity. Using receptor agonists and thrombin inhibitors, we separately examined the role of thrombin and its receptor in neuroprotection. We found that low concentrations of thrombin (1 nM) enhances neurite growth and branching, neuron viability, and protects against excitotoxic damage. In contrast, higher concentrations of thrombin (100 nM) are potentially detrimental to neuronal health as evidenced by inhibition of neurite growth. Lower concentrations of thrombin resulted in equivalent neuroprotection as the antifibrinolytic, aprotinin, and the direct thrombin inhibitor, argatroban. Interestingly, exogenous application of the species-specific thrombin inhibitor, antithrombin III, was detrimental to neuronal health; suggesting that some endogenous thrombin is necessary for optimal neuron health in our culture system. Activation of the thrombin receptor, protease-activated receptor-1 (PAR-1), via micromolar concentrations of the thrombin receptor agonist peptide, TRAP, did not adversely affect neuronal viability. An optimal concentration of thrombin exists to enhance neuronal health. Neurotoxic effects of thrombin do not involve activation of PAR receptors and thus separate pharmacologic manipulation of thrombin's receptor in the setting of direct thrombin inhibitors could be a potential neuroprotective strategy.

Duke Scholars

Published In

Neurochem Res

DOI

EISSN

1573-6903

Publication Date

November 2015

Volume

40

Issue

11

Start / End Page

2220 / 2229

Location

United States

Related Subject Headings

  • Thrombin
  • Sulfonamides
  • Receptors, Thrombin
  • Receptor, PAR-1
  • Rats, Sprague-Dawley
  • Rats
  • Pipecolic Acids
  • Peptide Fragments
  • Neuroprotective Agents
  • Neurons
 

Citation

APA
Chicago
ICMJE
MLA
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García, P. S., Ciavatta, V. T., Fidler, J. A., Woodbury, A., Levy, J. H., & Tyor, W. R. (2015). Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons. Neurochem Res, 40(11), 2220–2229. https://doi.org/10.1007/s11064-015-1711-1
García, Paul S., Vincent T. Ciavatta, Jonathan A. Fidler, Anna Woodbury, Jerrold H. Levy, and William R. Tyor. “Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons.Neurochem Res 40, no. 11 (November 2015): 2220–29. https://doi.org/10.1007/s11064-015-1711-1.
García PS, Ciavatta VT, Fidler JA, Woodbury A, Levy JH, Tyor WR. Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons. Neurochem Res. 2015 Nov;40(11):2220–9.
García, Paul S., et al. “Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons.Neurochem Res, vol. 40, no. 11, Nov. 2015, pp. 2220–29. Pubmed, doi:10.1007/s11064-015-1711-1.
García PS, Ciavatta VT, Fidler JA, Woodbury A, Levy JH, Tyor WR. Concentration-Dependent Dual Role of Thrombin in Protection of Cultured Rat Cortical Neurons. Neurochem Res. 2015 Nov;40(11):2220–2229.
Journal cover image

Published In

Neurochem Res

DOI

EISSN

1573-6903

Publication Date

November 2015

Volume

40

Issue

11

Start / End Page

2220 / 2229

Location

United States

Related Subject Headings

  • Thrombin
  • Sulfonamides
  • Receptors, Thrombin
  • Receptor, PAR-1
  • Rats, Sprague-Dawley
  • Rats
  • Pipecolic Acids
  • Peptide Fragments
  • Neuroprotective Agents
  • Neurons