Development of intracellular acidosis during cerebral ischemia and generation of free radicals during reperfusion are two mechanisms of brain injury that have received increasing attention in recent years. The overall goal of this proposal is to investigate the role of intracellular pH and oxygen-derived free radicals on the recovery of cerebral high energy phosphates, blood flow and electrical function following ischemia. We will use in vivo 31P nuclear magnetic resonance spectroscopy to track the recovery of cerebral ATP, phosphocreatine (PCr) and intracellular pH (pHi). We will simultaneously measure cerebral blood flow (CBF), O2 uptake, and somatosensory evoked potentials (SEP) as a quantitative measure of brain electrical function. We will study both complete and incomplete global cerebral ischemia produced by intracranial pressure elevations in dogs. To titrate recovery of electrical function (from normal to poor restoration), three ischemic durations will be produced so that effects of interventions can be studied in an injury-dose dependent manner. We will first determine whether the initial rate of recovery of ATP and PCr, as a marker of mitochondrial function, correlate better with SEP recovery than steady state recovery levels of ATP and PCr following various durations of complete and incomplete ischemia. We will then examine the influence of pHi achieved during ischemia and its rate of normalization during reperfusion on the rate of recovery of ATP, PCr and SEP. To manipulate pHi, blood glucose levels will be varied, thereby altering lactic acid production. Complete ischemia will be compared to incomplete ischemia, where the range of pHi alterations should be greater because of sustained glucose delivery during ischemia. The influence of hyperventilation, a clinical intervention frequently used, on recovery of pHi, ATP, PCr and SEP will also be studied. We will investigate the role of oxygen-derived free radicals first by indirectly measuring the generation of superoxide anion during reperfusion, and second by demonstrating that free radical scavengers (superoxide dismutase) and inhibitors of different free radical generating systems suppress superoxide appearance during reperfusion. We will then evaluate the efficacy of superoxide dismutase and catalase administration on the restoration of CBF, SEP, ATP and PCr. Finally, we will determine if acidosis potentiates free radical appearance and if scavengers can effectively reverse this detrimental effect of acidosis. These studies should enhance our understanding of ischemic-reperfusion injury mechanisms in brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS024394-01
Application #
3408944
Study Section
Neurology A Study Section (NEUA)
Project Start
1986-12-01
Project End
1989-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Maruki, Y; Koehler, R C; Eleff, S M et al. (1993) Intracellular pH during reperfusion influences evoked potential recovery after complete cerebral ischemia. Stroke 24:697-703;discussion 704
Kirsch, J R; Helfaer, M A; Haun, S E et al. (1993) Polyethylene glycol-conjugated superoxide dismutase improves recovery of postischemic hypercapnic cerebral blood flow in piglets. Pediatr Res 34:530-7
Backofen, J E; Koehler, R C; Harris, A P et al. (1991) Efficacy of Cushing response during development in sheep. Am J Physiol 261:H575-82
Hurn, P D; Koehler, R C; Norris, S E et al. (1991) Dependence of cerebral energy phosphate and evoked potential recovery on end-ischemic pH. Am J Physiol 260:H532-41
Eleff, S M; Maruki, Y; Monsein, L H et al. (1991) Sodium, ATP, and intracellular pH transients during reversible complete ischemia of dog cerebrum. Stroke 22:233-41
Matsumiya, N; Koehler, R C; Kirsch, J R et al. (1991) Conjugated superoxide dismutase reduces extent of caudate injury after transient focal ischemia in cats. Stroke 22:1193-200
Hurn, P D; Koehler, R C; Norris, S E et al. (1991) Bicarbonate conservation during incomplete cerebral ischemia with superimposed hypercapnia. Am J Physiol 261:H853-9
Helfaer, M A; Kirsch, J R; Haun, S E et al. (1991) Age-related cerebrovascular reactivity to CO2 after cerebral ischemia in swine. Am J Physiol 260:H1482-8
Matsumiya, N; Koehler, R C; Traystman, R J (1990) Consistency of cerebral blood flow and evoked potential alterations with reversible focal ischemia in cats. Stroke 21:908-16
Sieber, F E; Koehler, R C; Derrer, S A et al. (1990) Hypoglycemia and cerebral autoregulation in anesthetized dogs. Am J Physiol 258:H1714-21

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