The long-term objective of the research plan is to elucidate mechanisms of neuronal cell damage in the brain in conditions which are associated with a reduced cerebral supply of oxygen or glucose, or with pathologically enhanced neuronal activity and, thereby, to provide basic knowledge furthering rational clinical therapy of stroke, insulin shock, and epilepsy. To that end, such mechanisms are studied in well-controlled animal models of ischemia, hypoglycemia, and status epilepticus, models that allow long-term recovery and assessment of the density and distribution of the final cell damage incurred. These three conditions are studied since each of them has some unique features which, when studied singly or in combination, offer unique opportunities to dissect mechanisms of cell death. The projects are based on the working hypotheses that a disturbed cellular Ca2+ homeostasis forms a common mechanism of damage, that the density of energy failure determines the damage incurred by ischemia and hypoglycemia, and that acidosis is an important determinant of ischemic and epileptic brain damage. The research projects have the following three specific aims: (1) To determine the relationship between the remaining energy source and the density of cell damage incurred, (2) to assess the modulating influence of cellular acidosis (ischemia and status epilepticus) and alkalosis (hypoglycemia), and (3) to study the importance of Ca2+ triggered events, particularly lypolysis with accumulation of free fatty acids, proteolysis, and free radical formation. In addition, the problem of selective neuronal vulnerability is approached by lesioning experiments that may help to define functional connections which modulate the impact of ischemic, hypoclycemic, and epileptic insults.
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