PMID- 21361959 OWN - NLM STAT- MEDLINE DCOM- 20110610 LR - 20220331 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 117 IP - 3 DP - 2011 May TI - Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury. PG - 579-88 LID - 10.1111/j.1471-4159.2011.07228.x [doi] AB - 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 (alpha-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 alpha-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 alpha-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 alpha-alpha-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. CI - (c) 2011 The Authors. Journal of Neurochemistry (c) 2011 International Society for Neurochemistry. FAU - Mustafa, Ayman G AU - Mustafa AG AD - Spinal Cord & Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA. FAU - Wang, Juan A AU - Wang JA FAU - Carrico, Kimberly M AU - Carrico KM FAU - Hall, Edward D AU - Hall ED LA - eng GR - R01 NS046566-04/NS/NINDS NIH HHS/United States GR - P30 NS051220/NS/NINDS NIH HHS/United States GR - 1P30 NS051220/NS/NINDS NIH HHS/United States GR - P01 NS058484-03/NS/NINDS NIH HHS/United States GR - R01 NS046566/NS/NINDS NIH HHS/United States GR - P30 NS051220-04/NS/NINDS NIH HHS/United States GR - 1P01 NS058484/NS/NINDS NIH HHS/United States GR - P01 NS058484/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110322 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Chromans) RN - 0 (Neuroprotective Agents) RN - 0 (Piperazines) RN - 133681-84-2 (U 78517F) RN - EC 3.4.22.- (Calpain) SB - IM MH - Animals MH - *Brain Injuries/drug therapy/metabolism/pathology MH - Calpain/*pharmacology MH - Chromans/pharmacology/*therapeutic use MH - Cytoskeleton/*drug effects MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Lipid Peroxidation/*drug effects MH - Male MH - Mice MH - Neuroprotective Agents/pharmacology/*therapeutic use MH - Piperazines/pharmacology/*therapeutic use MH - Time Factors PMC - PMC3076544 MID - NIHMS277896 EDAT- 2011/03/03 06:00 MHDA- 2011/06/11 06:00 PMCR- 2012/05/01 CRDT- 2011/03/03 06:00 PHST- 2011/03/03 06:00 [entrez] PHST- 2011/03/03 06:00 [pubmed] PHST- 2011/06/11 06:00 [medline] PHST- 2012/05/01 00:00 [pmc-release] AID - 10.1111/j.1471-4159.2011.07228.x [doi] PST - ppublish SO - J Neurochem. 2011 May;117(3):579-88. doi: 10.1111/j.1471-4159.2011.07228.x. Epub 2011 Mar 22.