Previous studies from our laboratory indicate that traumatic brain injury (TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.