This amended translational grant application seeks support to pursue the central hypothesis that the use of posttraumatic hypothermia not only provides primary neuronal and vascular protection, but also extends a therapeutic window over which other therapies, previously identified to be neuroprotective in the early phases of injury, gain enhanced efficacy. Although to date, many successful therapeutic strategies have been identified in the laboratory to treat traumatic brain injury (TBI), they have not proved efficacious in brain-injured humans. This failure has been linked to the fact that in clinical trials these agents were administered too late in the posttraumatic course to exert significant protection. The current application is intellectually framed around the central premise that the use of mild posttraumatic hypothermic intervention provides not only enhanced brain and vascular protection but also extends the therapeutic window over which other protective agents can be used with enhanced efficacy. The proposed studies are based upon preliminary data that speaks to the credibility of this premise in traumatically brain-injured animals. Further, the proposed studies are coupled to the design of an ongoing NIH-funded clinical trial that is also assessing the efficacy of early mild hypothermic intervention. The studies proposed will be conducted in rats and micropigs subjected to fluid percussion brain injury. The effects of 33[unreadable]C hypothermic intervention upon TBI-impaired cerebral vascular reactivity will be assessed through functional studies performed via cranial windows, with parallel assessments of axonal damage in various brain white matter regions and tracts. Further, in the rodents, cognitive assessments will be performed. In addition to the use of hypothermic intervention, we will also employ combinational therapy using mild hypothermia, coupled to the delayed use of other agents previously recognized to be protective only ultra early postinjury. To this end, superoxide dismutase and the immunophilin ligands, FK506 and cyclosporin A, will be used based upon extensive laboratory data speaking to their usefulness in TBI and the fact that cyclosporin A is also currently being assessed in multicenter clinical trials. If successful, it is anticipated that these studies will be translated into full blown translational studies examining the protective effects of these strategies on multiple traumatically induced CNS abnormalities, while also considering a larger array of previously identified neuroprotective drugs. This application has immediate relevance to public health. The experimental paradigm using hypothermia following traumatic brain injury parallels important clinical trials ongoing in traumatically brain-injured humans. Additionally, if as posited, the use of hypothermia also extends the therapeutic window over which other neuroprotective compounds retain their efficacy, the findings of this study may have even more immediate clinical relevance.