The pathogenesis of ischemic brain injury is poorly understood. I plan to undertake detailed analyses of the cascade of aberrant microphysiological activities that occur during ischemia and recirculation, a process that has important clinical ramifications. Results from experimental stroke rsearch suggest that either lactic acidosis or disruption of cell calcium homeostasis may be fundamentally responsible for ischemic brain injury. However, little direct evidence exists to confirm these postulated roles for lactate and calcium. A highly reproducible model of severe forebrain ischemia developed in this laboratory will be used in this study. Work with this model has shown a selective vulnerability of neurons in space and time. Histological evidence of damage progresses for days. Microelectrodes sensitive to particular ions, gases, or organic chemicals (microsensors) will be used to test the hypothesis that temporally important local changes in ion and metabolite homeostasis may be detected and be causally related to selective vulnerability. We propose to measure and manipulate the hydrogen and calcium homeostasis and related variables in forebrain regions with varying sensitivity to ischemia during and after the interruption of blood flow. This information will be correlated to histological and electrophysiological characterization of the same areas. Existing microsensors for H+, K+, Ca++, Na+, and Cl- will be used in this study. In addition we expect to develop sensors for CO2, O2, lactate, and glucose.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07NS000767-04
Application #
3078118
Study Section
Neurological Disorders Program Project Review A Committee (NSPA)
Project Start
1983-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Kraig, R P; Chesler, M (1990) Astrocytic acidosis in hyperglycemic and complete ischemia. J Cereb Blood Flow Metab 10:104-14
Chesler, M; Kraig, R P (1989) Intracellular pH transients of mammalian astrocytes. J Neurosci 9:2011-9
Kraig, R P (1988) Acid-induced injury in elasmobranch brain. Neurosci Lett 90:119-24
Plum, F; Kraig, R P; Pulsinelli, W A (1988) Compartmentation of acid-base balance in brain during complete ischemia. Neurochem Pathol 9:139-44
Kraig, R P; Cooper, A J (1987) Bicarbonate and ammonia changes in brain during spreading depression. Can J Physiol Pharmacol 65:1099-104
Petito, C K; Kraig, R P; Pulsinelli, W A (1987) Light and electron microscopic evaluation of hydrogen ion-induced brain necrosis. J Cereb Blood Flow Metab 7:625-32
Chesler, M; Kraig, R P (1987) Intracellular pH of astrocytes increases rapidly with cortical stimulation. Am J Physiol 253:R666-70
Kraig, R P; Wagner, R J (1987) Acid-induced changes of brain protein buffering. Brain Res 410:390-4
Kraig, R P; Pulsinelli, W A; Plum, F (1985) Heterogeneous distribution of hydrogen and bicarbonate ions during complete brain ischemia. Prog Brain Res 63:155-66
Kraig, R P; Pulsinelli, W A; Plum, F (1985) Hydrogen ion buffering during complete brain ischemia. Brain Res 342:281-90