Abstract
It is now recognized that neuronal death after hypoglycemia is not a simple result of energy failure resulting from hypoglycemia, but is instead the result of a cell death program that is initiated by hypoglycemia. It will be important to fully understand the sequence of events in this cell death pathway in order to identify late, downstream points at which intervention can be made. A rat model of insulin-induced hypoglycemia was used to assess vesicular zinc release, superoxide production, and the therapeutic potential of a superoxide dismutase (SOD) mimetic, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). Hypoglycemia was induced by 15 U/kg insulin injection and terminated by glucose infusion after 30 minutes of isoelectric EEG. Vesicular zinc staining with N (6 methoxy 8 quinolyl) para toluenesulfonamide (TSQ) showed that glucose reperfusion potentiated vesicular zinc release from the hippocampus, and that this release is prevented by the neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7NI). Dihydroethidine (dHEt) detection of superoxide showed superoxide production to be only minimally increased during hypoglycemia, but markedly increased by re-infusion of glucose. This superoxide production was attenuated by intraventricular injection of a zinc chelator, disodium calcium ethylene-diamine tetraaceatic acid (CaEDTA), suggesting that zinc release is upstream event of superoxide production. Treatment with TEMPOL before the glucose reperfusion blocked production of superoxide and reduced neuronal death by more than 60% in hippocampus and cortex when evaluated 1 week after the hypoglycemia. These results suggest that glucose reperfusion-induced vesicular zinc release and subsequent superoxide production are major factors mediating hypoglycemic neuronal death, and that superoxide mimetics can rescue neurons that would otherwise die after severe hypoglycemia. Juvenile Diabetes Research Foundation (SWS, JDRF3-2004-298), Department of Veterans Affairs, and NIH (RAS, NS41421, NS051855-01).
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