Neurologic outcome remains the major limiting factor in the quality of life for survivors of cardiac arrest and subsequent resuscitation. This project is an intergrated attack on the causes and prevention of neurological damage during and after cardiac arrest, utilizing physiological, biochemical, and molecular biological approaches. Global brain ischemia and reperfusion in dogs will be produced by cardiac arrest followed by resuscitation. Brain nuclear and mitochondrial DNA, lipids, iron, tissue ions, and morphology will be studied at progressive times of ischemia and reperfusion. The same approach will be used to evaluate therapeutic agents against biochemical and structural injury, and the most promising will be evaluated for their effect on neurologic outcome. The tissue and cellular biochemistry of brain is dramatically affected by ischemia and reperfusion. It is evident that neuronal Ca2+ overloading during ischemia leads to activation of phospholipases intracellularly, and generation of xanthine oxidase in brain capillaries. Ca2+ overloading has also been proposed to activate nucleases that generate single stranded DNA regions. Following these ischemic events, we propose a crucial sequence of tissue injury during reperfusion (Appendix Fig. I): 1) superoxide is generated and releases ferrous iron from ferritin; 2) despite initial recovery of adenylate charge and Na, K, and Ca gradients, iron- mediated oxygen radical reactions cause extensive damage to cell membranes, resulting in loss of selective membrane permeability; 3) oxygen radicals concurrently cause conversion of DNA single stranded regions that accumulated during ischemia to lethal double strand DNA breaks; and 4) these events are reflected in progressive ultrastructural injury observed during reperfusion as well as the irreversible neurologic injury observed and may be amenable to treatment with iron chelators and/or radical scavengers.
| DeGracia, D J; O'Neil, B J; Frisch, C et al. (1993) Studies of the protein synthesis system in the brain cortex during global ischemia and reperfusion. Resuscitation 25:161-70 |
| Krause, G S; Tiffany, B R (1993) Suppression of protein synthesis in the reperfused brain. Stroke 24:747-55;discussion 755-6 |
| White, B C; Daya, A; DeGracia, D J et al. (1993) Fluorescent histochemical localization of lipid peroxidation during brain reperfusion following cardiac arrest. Acta Neuropathol 86:1-9 |
| DeGracia, D J; O'Neil, B J; White, B C et al. (1993) Insulin induces tyrosine phosphorylation of a 90-kDa protein during postischemic brain reperfusion. Exp Neurol 124:351-6 |
| White, B C; Grossman, L I; Krause, G S (1993) Brain injury by global ischemia and reperfusion: a theoretical perspective on membrane damage and repair. Neurology 43:1656-65 |
