We examined glutamate-mediated neurotoxicity in cortical cell cultures pretreated with l-5 &ml tetanus toxin to attenuate the Ca*+-dependent release of neurotransmitters. Efficacy of the tetanus toxin pretreatment was suggested by blockade of electrical burst activity induced by Mg*+ removal and by reduction of glutamate efflux induced by high K+. Tetanus toxin reduced neuronal injury produced by brief exposure to elevated extracellular K+ or to glutamate, situations in which release of endogenous excitatory neurotransmitter is likely to play a role. Furthermore, although glutamate efflux evoked by anoxic conditions may occur largely via Ca2+-independent transport, tetanus toxin attenuated both glutamate efflux and neuronal injury following combined oxygen and glucose deprivation. With prolonged exposure periods, the neuroprotective efficacy of tetanus toxin was comparable to that of NMDA receptor antagonists. Presynaptic inhibition of Ca2+-dependent glutamate release may be a valuable approach to attenuating hypoxic-ischemic brain injury. introduction

Microdialysis measurements indicate that substantial amounts of glutamate accumulate in the extracellular space during cerebral hypoxia-ischemia in vivo (Benveniste et al., 1984), a key event thought to trigger excitotoxic overactivation of postsynaptic glutamate receptors and subsequent neuronal death (Rothman and Olney, 1987; Meldrum et al., 1987; Choi, 1988). Both decreased cellular glutamate uptake and increased glutamate efflux likely contribute to this pathological glutamate accumulation. The mechanism underlying impaired glutamate uptake is defined: nerve terminals and glia remove extracellular glutamate by energy-dependent processes(Schousboe, 1981) and will fail in this task when high energy phosphate stores become depleted. On the other