The pathophysiology of hypoxic neuronal death, which is difficult to study in vivo, was further defined in vitro by placing dispersed cultures of rat hippocampal neurons into an anoxic atmosphere. Previous experiments had demonstrated that the addition of high concentrations of magnesium, which blocks transmitter release, protected anoxic neurons. These more recent experiments have shown that y-D-glutamylglycine (DGG), a postsynaptic blocker of excitatory amino acids, was highly effective in

more »

... venting anoxic neuronal death. DGG also completely protected the cultured neurons from the toxicity of exogenous glutamate (GLU) and aspartate (ASP). In parallel physiology experiments, DGG blocked the depolarization produced by GLU and ASP, and dramatically reduced EPSPs in synaptically coupled pairs of neurons. These results provide convincing evidence that the synaptic release of excitatory transmitter, most likely GLU or ASP, mediates the death of anoxic neurons. This result has far-reaching implications regarding the interpretation of the existing literature on cerebral hypoxia. Furthermore, it suggests new strategies that may be effective in preventing the devastating insults produced by cerebral hypoxia and ischemia in man. Cerebral hypoxia, either as an isolated event, or as a concomitant of occlusive cerebrovascular disease, perinatal asphyxia, or cardiorespiratory failure, is a frequent cause of human neurological injury. On occasion, the deficits produced by hypoxia are reversible, but irreversible brain damage is a far more common event. Despite the importance of the problem, the pathophysiology of hypoxic brain injury has not yet been determined, although it appears that altered calcium homeostasis, elevated free fatty acid concentrations, accumulation of eicosanoids, and increased extracellular lactic acid all contribute to neuronal death (Siesjo, 1981; Raichle, 1983). However, resolving all of the factors responsible for pure hypoxic brain injury has remained difficult because hypoxia in vivo is invariably associated with hypotension, hypercarbia, and acidosis, which are all potentially damaging. Recent in vitro observations have provided new insights into the pathophysiology of neuronal injury pro-