Project Details
Description
This application proposes four projects and core facilities to investigate
mechanisms of CNS injury. Project 1 Experimental Therapy of Spinal Cord
Injury. We recently discovered that cyclosporin A (CsA) reduces responses,
releases vasodilatory and inflammatory substances, and modulates
neurotransmitter receptors and release. We propose to study the role of
calcineurin in spinal cord injury. The experiments will compare the
effects of CsA, FK506 (another calcineurin inhibitor), alone and in
combination with rapamycin (an antagonist of K506 (another calcineurin
inhibitor), alone and in combination with rapamycin (an antagonist of FK506
inhibition of calcineurin), on spinal cord ionic shifts, lesion volumes,
motor recovery, blood flow, and serotonin-,GABA- and glutamate-induced
spinal excitability and injury. Project 2. Acid-base homeostasis in brain
injury. The mechanisms and consequences of pH changes in injured tissues
are not well-understood. We will measure pH, PCO2, HCO3, and CO32 in
ischemic brains and injured spinal cords, to determine the role of buffer
capacity, lactoacidosis, and carbonic anhydrase in the pH changes. We
propose that pH shifts modulate NMDA receptors and that interstitial
buffering influences the rate and magnitude of spreading depression and
ischemic injury in brain slices. Using on-selective microelectrodes,
voltage clamp, and spectrophotometric methods, we will test the hypothesis
that voltage-dependent Na:HCO3 co-transport governs H+, Na+, and HCO3-
distribution across astrocytic membranes in normo- and hyperglycemic
ischemia.
Project 3. Ascorbate and glutathione in CNS Injury. We hypothesize that
ascorbate (Asc) and glutathione (GSH) loss contributes to brain cell
vulnerability to oxidative damage. Extracellular Asc will be measured in
hypoxic brain slices and in ischemic cerebral cortex after middle cerebral
artery occlusion. Intracellular Asc will be estimated from extracellular
volumes and total tissue levels. Preliminary studies suggest that Asc and
GSH are localized in neurons and astrocytes respectively, that both Asc and
GSH decline with age and are lower in females. We will confirm these
results, determine whether hypoxia and age compromises Asc homeostasis,
assess protective effects of Asc and GSH in hypoxic brain slices, identify
mechanisms of Asc and GSH loss in ischemia, and correlate tissue damage
with Asc loss in male and females.
Project 4. Water compartmentalization in Ischemia. The objective of this
project is to understand how water shifts between extra- and intracellular
compartments in ischemic brain tissues. Water shifts will be assessed with
extracellular tracers, ion-elective microelectrodes, and weighing-drying
method. We will manipulate extracellular ionic levels and block ionic
transport and glutamate receptors. Water movements will be investigated in
slices from aged animals. The role of the Na:HCO3 cotransport will be
assessed. Light scattering and Na-K changes will be compared with wet-dry
weight and tracer measurements.
Status | Finished |
---|---|
Effective start/end date | 9/1/96 → 5/31/03 |
Funding
- National Institute of Neurological Disorders and Stroke
ASJC
- Clinical Neurology
- Neurology
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