ISCHEMIC PRECONDITIONING--MECHANISMS OF NEUROPROTECTION

Recent evidence in heart and brain suggest that mild ischemic episodes may limit the damage from subsequent ischemic insults. This program of research is directed toward understanding the mechanisms of such ischemic preconditioning. Understanding these mechanisms may allow pharmacological access to this protective state during surgical procedures. This understanding may also offer unique new insights into the basic mechanisms of ischemic injury and into potential therapeutic interventions that may ameliorate the consequences of cerebral ischemia. Goals of this research are to test four broad hypotheses. First we propose that a sub-lethal period of ischemia followed by a brief referfusion period will protect against a subsequent global ischemic insult. This hypothesis will be tested in an in vivo model of transient forebrain global ischemia in rats. The intensity of ischemic neuronal damage will be assessed different times. The second hypothesis relates to the mechanism of neuroprotection afforded by IPC. Concentration will be upon derangements produced by global ischemia that are functional (changes in ion homeostasis as indicated by extracellular potassium ion activity, evoked potentials; and metabolic activities as signalled by local blood flow, and neurotransmitter releases). The third hypothesis relates to the role of adenosine during IPC. In vivo studies will determine whether adenosine plays a key role during IPC, as has been established in cardiac ischemia. These studies will determine the neuroprotective role of adenosine on ion homeostasis, electrical activity, blood flow, neurotransmitter release and histopathology. Finally, IPC will be studied by emphasizing intracellular mechanisms. The hypothesis is that IPC promotes a better maintenance of neuronal energy charge by inhibiting electrical activity. Intracellular studies will determine effect of IPC on different conductances of the pyramid cells of the Ca1 hippocampal slices. Definition of IPC will likely provide an important step toward understanding mechanisms of ischemic damage and tolerance. It is toward this goal that the present research is proposed.