The long-term goal of this project is to determine the role of tissue acid- base and metabolic derangements in the evolution of infarction following focal stroke. Experimental focal ischemia is more relevant to most human strokes than are global models. The information gained from focal models of ischemia, however, has been discouraging owing to the variability in the size and location of the lesion in existing models. Areas of reduced blood flow surrounding the ischemic focus following middle cerebral artery (MCA) occlusion apparently can survive the initial insult, but eventually succumb to some secondary event. While the energy stores are immediately depleted in the ischemic focus, those in the perifocal region or penumbra (P) are near normal despite a significant accumulation of lactate. This condition resembles that of spreading depression which is known to be metabolically costly, and certainly the P is already at risk owing to low blood flow. The perifocal region becomes infarcted within 24 H and the mechanisms of cell death are only a matter of speculation. What is clear is that the death of the P contributes to long-term disability and that effective treatment of focal stroke remain elusive. The problems encountered in the investigation of metabolism in focal stroke have been resolved. The perifocal and focal regions in brains frozen in situ now can be identified and dissected on the basis of quantitative blood flow values. Metabolites in mug pieces of tissue can be measured readily using microquantitative histochemistry. Combining these two methodologies provides an unique approach to study of the metabolic derangements in the penumbra. The immediate goal of this application is to determine if the disparate metabolic response of the two contiguous regions is the reason for the death of the P. Neurotransmitters, lactic acid and potassium are released during ischemia and each could diffuse to the adjacent P area, creating an additional work load. The additional energy demands on the P, its compromised blood flow, and an increasing energy imbalance would lead to energy failure, loss of cell volume control and infarction. This possibility will be tested by the following aims: 1) to determine in the P and ischemic core the changes in energy metabolism, acid-base balance, water content and neurotransmitter metabolism at various times after MCA occlusion, 2) to measure the extent of edema formation, either directly in dissected cortical tissues or by proton MRI, and to correlate these changes with alterations in electrolyte levels from discretely dissected tissues and 3) to determine if hyperglycemia, which is known to decrease pHi and increase lactate levels in ischemic areas, will act similarly in the penumbra to a) either hasten the onset of or increase the size of the infarct and b) affect edema formation. Other treatments targetted to putative pathogenic events will also be tested. The information gained from these experiments will help provide a basis for developing an intervention which will neutralize the influence of ischemic tissue on neighboring tissue and thereby improve the outcome following focal ischemia by minimizing the extent of the infarct.
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