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Journal of Neuroscience, Vol 15, 5389-5401, Copyright © 1995 by Society for Neuroscience
Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults
PJ Vaughan, CJ Pike, CW Cotman and DD Cunningham
Department of Microbiology and Molecular Genetics, University of California, Irvine 92717, USA.
Thrombin is a multifunctional serine protease that is rapidly produced from
prothrombin at sites of tissue injury and catalyzes the final steps in
blood coagulation. Thrombin also regulates gene expression and process
outgrowth in neurons and astrocytes and stimulates proliferation of
astrocytes. Since thrombin is produced immediately upon breakdown of the
blood-brain barrier we examined its effects on astrocytes and neurons
cultured under conditions which resemble those found in vivo following
cerebrovascular injury. These studies showed that thrombin markedly
protected rat primary astrocytes from cell death induced by hypoglycemia or
oxidative stress. Thrombin also protected rat primary hippocampal neurons
from cell death produced by hypoglycemia or growth supplement deprivation.
Synthetic peptides which directly activate the thrombin receptor also
protected astrocytes and neurons from these environmental insults,
demonstrating that the thrombin effects were mediated through the thrombin
receptor. In contrast to these results with stressed cells, high
concentrations of thrombin killed both astrocytes and neurons cultured
under normal conditions. All of the effects of thrombin on astrocytes and
neurons were blocked by the brain thrombin inhibitor, protease nexin-1
(PN-1). This shows that the effects required the proteolytic activity of
thrombin and is consistent with the known proteolytic mechanism by which
thrombin activates its receptor. These results indicate that thrombin and
PN-1 may regulate the viability of both astrocytes and neurons in early
moments following trauma to the CNS or other conditions that alter the
blood-brain barrier.
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