Pharmacological inhibition of lipid peroxidation attenuates calpain‐mediated cytoskeletal degradation after traumatic brain injury

J. Neurochem. (2011) 117 , 579–588. Abstract Free radical‐induced lipid peroxidation (LP) is critical in the evolution of secondary injury following traumatic brain injury (TBI). Previous studies in our laboratory demonstrated that U‐83836E, a potent LP inhibitor, can reduce post‐TBI LP along with an improved maintenance of mouse cortical mitochondrial bioenergetics and calcium (Ca 2+ ) buffering following severe (1.0 mm; 3.5 m/s) controlled cortical impact TBI (CCI‐TBI). Based upon this preservation of a major Ca 2+ homeostatic mechanism, we have now performed dose‐response and therapeutic window analyses of the ability of U‐83836E to reduce post‐traumatic calpain‐mediated cytoskeletal (α‐spectrin) proteolysis in ipsilateral cortical homogenates at its 24 h post‐TBI peak. In the dose‐response analysis, mice were treated with a single i.v. dose of vehicle or U‐83836E (0.1, 0.3, 1.3, 3.0, 10.0 or 30.0 mg/kg) at 15 min after injury. U‐83836E produced a dose‐related attenuation of α‐spectrin degradation with the maximal decrease being achieved at 3.0 mg/kg. Next, the therapeutic window was tested by delaying the single 3 mg/kg i.v. dose from 15 min post‐injury out to 1, 3, 6 or 12 h. No reduction in α‐spectrin degradation was observed when the treatment delay was 1 h or longer. However, in a third experiment, we re‐examined the window with repeated U‐83836E dosing (3.0 mg/kg i.v. followed by 10 mg/kg i.p. maintenance doses at 1 and 3 h after the initial i.v. dose) which significantly reduced 24 h α‐α‐spectrin degradation even when treatment initiation was withheld until 12 h post‐TBI. These results demonstrate the relationship between post‐TBI LP, disruptions in neuronal Ca 2+ homeostasis and calpain‐mediated cytoskeletal damage.