Hypoglycemia is a common but serious problem among type1 and type 2 diabetic patients receiving intensive treatment with glucose-lowering drugs such as insulin or sulfonylurea. Moderate hypoglycemia is occurring 0.1-0.3 episode/patient per day and is usually corrected by patients themselves or just ignored. However, severe hypoglycemia causes unconsciousness and it may lead to neuronal injury in the cerebral cortex and hippocampus. Hypoglycemic neuronal death is resulted from a cascade of several events after prolonged period of lack of glucose since brain exclusively use glucose. Sustained release of glutamate from presynaptic terminals into the extracellular space and activation of glutamate receptors has been suggested as a necessary upstream event in this neuron death cascade. Also mitochondrial membrane permeability, PARP-1 activation and NADPH oxidase activation-induced ROS production have been shown to be possible downstream events. Our lab has undertaken studies to establish whether vesicular zinc release and subsequent zinc translocation into postsynaptic neurons is an important upstream step in this hypoglycemia-induced neuron death process. Using an animal model of insulin-induced hypoglycemia we have shown that: (I) vesicular zinc is released from hippocampal mossy fiber terminals; (II) intracellular zinc accumulation is induced in the hippocampal neurons; (III) neuronal death is reduced by zinc chelation or zinc transporter gene deletion; (IV) PARP-1 activation is reduced by zinc chelation; (V) ROS production is reduced by zinc chelation after hypoglycemia and glucose reperfusion (HG/GR); and (VI) hypothermia prevented hypoglycemia-induced zinc release and neuron death. Together, these results suggest that zinc translocation is an upstream step linking HG/GR to PARP-1 activation, to NADPH oxidase activation and neuronal death in brain regions containing high concentrations of vesicular zinc.