Oxidative Damage and Calcium-Activated Proteolytic Biomarkers After Traumatic Brain Injury and Effects of Cyclosporine A

The drug cyclosporine A (CsA) has been demonstrated to attenuate posttraumatic neurodegeneration in rodent TBI models, and to do this by reducing free radical lipid peroxidative (LP) damage, mitochondrial dysfunction and impairment of intracellular calcium (Ca++) homeostatic mechanisms which leads to proteolytic degradation of brain proteins. Subsequently, CsA was the subject of an NINDS supported Phase IIa clinical trial in “severe” TBI patients that showed the drug to be safe, and some indication of neuroprotective efficacy was observed as CsA produced a dose-related improvement in outcome. This KSCHIRT proposal is directed at the exploration of potential TBI biomarkers that might serve as “diagnostic” indicators of the severity and time course of posttraumatic LP and proteolytic damage and “theranostic” indices of the early response to neuroprotective drug therapy in further TBI clinical trials with CsA and other neuroprotective therapies. Firstly, the LP byproducts 5&15 F2T isoprostanes (IsoP) formed from arachidonic acid (AA) and F4 neuroprostanes (NP) formed from peroxidized docosahexaenonic acid (DHA) will be measured in plasma and CSF samples. Secondly, we will measure the proteolytic fragments of the cytoskeletal protein á-spectrin in CSF as an index of axonal degeneration. All of the analytical techniques are established in the PI’s laboratory. University of Kentucky Institutional Review Board approval has been obtained for this project. This grant will allow a validation of the use of these peroxidative and cytoskeletal biomarkers in larger NINDS-sponsored multi-center Phase IIb and Phase III CsA TBI clinical trials.