We use a new in vitro model to examine the effect of mechanical deformation on neurons. We examined acute changes in cytosolic calcium concentrations ([Ca(2+)](i)) caused by a rapid stretch of cultured hippocampal neurons, using mechanical loading conditions that mimic brain deformations during trauma. We found that stretch-injury of neurons induces a strain-dependent increase in [Ca(2+)](i). Remarkably, the extent of this calcium response exceeded the levels initiated by chemical toxicity with NMDA (100 microM) or glutamate (5 mM) exposure. Propidium iodide labeling at 24 h following stretch showed neuronal death occurred only at the most severe level of mechanical injury. Although NMDA-induced toxicity could be inhibited in calcium free media or by treatment with MK-801, stretch-induced neuronal death was not similarly reduced with either treatment. Unexpectedly, reduction of the acute stretch-induced calcium transient with calcium-free media or MK-801 resulted in an increase in neuronal death at lower stretch levels. These data suggest that mechanical stretch can initiate calcium influx in hippocampal neurons, but substantially modulating the early calcium flux from the extracellular space or through the NMDA channel does not provide an effective means for improving neuronal survival.