This program of research is directed toward understanding links among pathophysiological events and histopathology after focal brain ischemia. The importance of this research stems from the fact that little is known of the natural history and consequences of the physiological changes produced by focal ischemia. This is due, in part, to the complex heterogeneities of pathophysiology and histopathology as these extend outward from the focal ischemic core. Also complicating such studies is that pathophysiology and histopathology are not static but vary with time as cells are incorporated into the ischemic core or into more normal regions. Focal ischemia is emphasized as a research target because: a) it is the most common of ischemic brain insults in patients; and b) there is hope that the neurological defects of focal ischemia may be limited if cells can be spared from being incorporated into the central, necrotic zone by halting the progression of pathophysiological changes in peri infarct tissues. Goals of this research are to test three broad hypotheses. Through specific experiments, our objective is to provide temporal and spatial definition to the consequences of focal ischemia produced by middle cerebral artery occlusion (MCAo) in rat brain. Concentration will be upon derangements produced by MCAo that are functional (changes in ion homeostasis as indicated by extracellular potassium ion activity; and metabolic activities as signalled by local blood flow, tissue oxygen tension and reduction/oxidation shifts of cytochrome oxidase) and histopathological (infarction or sporadic neuronal injury at locally demarcated sites). Hypotheses are: 1) ionic derangements occur in the ischemic core, and in zones of the penumbra and the peripenumbra after MCAo. These derangements are not static but vary with time after focal ischemia. Testing this hypothesis will give fundamental definition to potassium ion activity after MCAo; 2) spreading depression like depolarization waves promote loss of ion homeostasis and histopathology after focal ischemia; and 3) focal ischemia promotes residual metabolic dysfunction in penumbral areas. Within each hypothesis are specific protocols which will better resolve the progression of pathophysiological events after focal ischemia, and contribute to defining mechanisms by which the ischemic core may expand into penumbral regions or by which this expansion may be halted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032167-03
Application #
2445801
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1995-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Perez-Pinzon, M A; Born, J G (1999) Rapid preconditioning neuroprotection following anoxia in hippocampal slices: role of the K+ ATP channel and protein kinase C. Neuroscience 89:453-9
Centeno, J M; Orti, M; Salom, J B et al. (1999) Nitric oxide is involved in anoxic preconditioning neuroprotection in rat hippocampal slices. Brain Res 836:62-9
Sick, T J; Xu, G; Perez-Pinzon, M A (1999) Mild hypothermia improves recovery of cortical extracellular potassium ion activity and excitability after middle cerebral artery occlusion in the rat. Stroke 30:2416-21;discussion 2422
Sick, T J; Tang, R; Perez-Pinzon, M A (1999) Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res 821:400-6
Perez-Pinzon, M A; Xu, G P; Born, J et al. (1999) Cytochrome C is released from mitochondria into the cytosol after cerebral anoxia or ischemia. J Cereb Blood Flow Metab 19:39-43
Perez-Pinzon, M A; Vitro, T M; Dietrich, W D et al. (1999) The effect of rapid preconditioning on the microglial, astrocytic and neuronal consequences of global cerebral ischemia. Acta Neuropathol (Berl) 97:495-501
Perez-Pinzon, M A; Mumford, P L; Carranza, V et al. (1998) Calcium influx from the extracellular space promotes NADH hyperoxidation and electrical dysfunction after anoxia in hippocampal slices. J Cereb Blood Flow Metab 18:215-21
Sick, T J; Feng, Z C; Rosenthal, M (1998) Spatial stability of extracellular potassium ion and blood flow distribution in rat cerebral cortex after permanent middle cerebral artery occlusion. J Cereb Blood Flow Metab 18:1114-20
Perez-Pinzon, M A; Mumford, P L; Sick, T J (1998) Prolonged anoxic depolarization exacerbates NADH hyperoxidation and promotes poor electrical recovery after anoxia in hippocampal slices. Brain Res 786:165-70
Perez-Pinzon, M A; Mumford, P L; Rosenthal, M et al. (1997) Antioxidants, mitochondrial hyperoxidation and electrical recovery after anoxia in hippocampal slices. Brain Res 754:163-70

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