IMPORTANCE OF THE BLOOD-BRAIN BARRIER IN STROKE

Project: Research project

Description

The proposed studies are planned in rats to examine the consequences of
vascular thrombosis on remote microvascular function and to determine
pathomechanisms. Recently, we have documented in two models of vascular
thrombosis, acute alterations in the blood-brain barrier (BBB) which are
associated with widespread hemodynamic consequences. The acute and more
chronic ultrastructural consequences of embolic stroke on the
microvasculature and brain parenchyma will be first investigated following
common carotid artery thrombosis (CCA). Histopathological outcome will be
studied with scanning and transmission electron microscopic procedures
combined with vascular permeability studies using horseradish peroxidase.
Autoradiographic strategies using labeled platelets and neutrophils will be
conducted to complement morphological findings. We hypothesize that
platelet emboli and other blood-borne substances are released into the
blood stream following CCA thrombosis leading to microvascular occlusion,
increased vascular permeability, and in some cases tissue destruction. Pre-
liminary data also demonstrate that this thrombogenically activated blood
can induce widespread depressions in local cerebral blood flow (1CBF) in
both donor and recipient rats. We hypothesize that serotonin, released from
aggregating platelets, crosses a damaged BBB barrier, leading to
vasoconstriction and decreased 1CBF. Next, in a reproducible model of
neocortical microvascular thrombosis, we will determine the significance of
BBB alterations on the hemodynamic and histopathological consequences of
this insult. We will determine whether histamine is responsible for the
hyperemic phase of the evolving infarct and changes in vascular
permeability. The pathomechanisms of remote depression of 1CBF following
thrombotic stroke will be investigated using regional microdialysis to
measure levels of vasoactive substances in the extracellular fluid of
remote brain regions. Selective antagonists directed at histamine,
serotonin and norepinephrine will be used to alter the hemodynamic conse-
quences and histopathological outcome of these thrombotic insults. The
complete characterization of the microvascular responses to vascular
thrombosis and the importance of these vascular events on histopathological
outcome should contribute to our understanding of the pathophysiology of
cerebrovascular disease.
StatusFinished
Effective start/end date8/1/905/31/05

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $300,000.00
  • National Institutes of Health: $288,110.00
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $167,030.00
  • National Institutes of Health: $287,500.00
  • National Institutes of Health: $300,000.00
  • National Institutes of Health
  • National Institutes of Health: $288,630.00
  • National Institutes of Health: $153,232.00
  • National Institutes of Health: $144,710.00
  • National Institutes of Health: $266,373.00
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Stroke
Carotid Artery Thrombosis
Hemodynamics
Blood-Brain Barrier
Blood Platelets
Thrombosis
Cerebrovascular Circulation
Capillary Permeability
Brain
Blood Vessels
Histamine
Serotonin
Transient Ischemic Attack
Embolism
Extracellular Fluid
Microdialysis
Horseradish Peroxidase
Norepinephrine
Nitric Oxide Synthase Type III
Neutrophils

ASJC

  • Medicine(all)
  • Neuroscience(all)