We studied the effects of a 6-min potassium depolarization injury produced by 60 mM KCl and 1.8 mM or 5.8 mM extracellular CaCl2 on tau protein levels in primary rat septo-hippocampal cultures. One day after injury, Western blot analyses revealed a calcium dependent loss of tau protein of approximately 50% of control values. Loss of tau protein was associated with calpain 1 mediated breakdown products to alpha-spectrin. Calpain inhibitors 1 and 2, applied immediately after depolarization injury and available to cultures for 24 h reduced depolarization induced degradation of tau protein to approximately 35% or 25% of control values, respectively. We propose that brief potassium depolarization causes degradation of tau protein, possibly due to calpain activation. Thus, calpain inhibitors could represent a viable strategy for preserving the cytoskeletal structure of injured neurons.