Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury
Version of Record online: 22 MAR 2011
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Volume 117, Issue 3, pages 579–588, May 2011
How to Cite
Mustafa, A. G., Wang, J. A., Carrico, K. M. and Hall, E. D. (2011), Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury. Journal of Neurochemistry, 117: 579–588. doi: 10.1111/j.1471-4159.2011.07228.x
- Issue online: 12 APR 2011
- Version of Record online: 22 MAR 2011
- Accepted manuscript online: 1 MAR 2011 06:09AM EST
- Received August 31, 2010; revised manuscript received February 22, 2011; accepted February 23, 2011.
- lipid peroxidation;
- traumatic brain injury;
J. Neurochem. (2011) 117, 579–588.
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 (Ca2+) buffering following severe (1.0 mm; 3.5 m/s) controlled cortical impact TBI (CCI-TBI). Based upon this preservation of a major Ca2+ 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 Ca2+ homeostasis and calpain-mediated cytoskeletal damage.