Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury - PubMed (original) (raw)
Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury
Ayman G Mustafa et al. J Neurochem. 2011 May.
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.
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Figures
Figure 1
U-83836E dose-response analysis of the effects of a single i.v. dose administered at 15 min after CCI-TBI in male mice on α-spectrin degradation in injured cortical tissue as assessed by quantitative western blotting of the calpain-specific 145 kDa and the mixed calpain/caspase 3-generated 150 kDa α-spectrin breakdown products at their 24 h peak. This was a two part study in which Part 1 involved testing the three lower doses whereas in Part 2 the higher three doses were examined. The three highest doses; 3.0, 10.0 and 30.0 mg/kg doses significantly reduced both SBDPs compared to their paired vehicle-treated group. Representative western blots are displayed below the graphs (LC stands for loading control). N = 10 animals/group; values = mean (±SD); one-way ANOVA followed by Dunnett’s post hoc test: * p < 0.05 vs. vehicle.
Figure 2
Therapeutic window analysis of the effects of a single 3.0 mg/kg i.v. dose of U-83836E, administered at 1, 3, 6 or 12 h after CCI-TBI in male mice on α-spectrin degradation in injured cortical tissue as assessed by quantitative western blotting of the calpain-specific 145 kDa and the mixed calpain/caspase 3-generated 150 kDa α-spectrin breakdown products at their 24 h peak. Values = mean (±SD) (N=10 mice/group) following administration of a single dose of U-83836E at either 1, 3, 6, or 12 h post-injury. A one-way ANOVA did not reveal a statistically significant difference across experimental groups in regards to the 145 and 150 kD SBDPs. Representative western blots are displayed below the graphs (LC stands for loading control).
Figure 3
Therapeutic window analysis of a multiple dose regimen of U-83836E initiated at either 1, 3, 6, 9, 12, or 18 h post-injury as measured by calpain-mediated α-spectrin proteolysis 24 h following severe CCI. The initial dose was 3mg/kg i.v followed one hour later by a 10mg/kg i.p maintenance dose. Two hours after the second dose, a third dose of 10mg/kg i.p was also administered. This was a two part study in which Part 1 involved testing of treatment delays of 1, 3 and 6 h whereas Part 2 involved a repeat of the 1 h treatment delay as well as 9, 12 and 18 h delays. Values = mean (±SD) for the 145 and 150 kDa SBDPs with N = 10 mice/group. One-way ANOVAs revealed a statistically significant difference across experimental groups in both Part 1 and Part 2. Subsequent post hoc analysis revealed that the mice treated with multiple doses of U-83836E at, 1, 3, 6, 9, or 12 h post-injury all had a significantly (p<0.05) lower mean levels of the 145 and 150 kDa SBDPs compared with the paired vehicle-treated groups. However, even the group treated with multiple doses of U-83836E beginning at 18 h after injury did display a lower level of the 150 kDa SBDP, but not that of the calpain-specific 145 kDa fragment compared to the vehicle-treated group. Statistical differences (one-way ANOVA and Dunnett’s post hoc test), *p<0.01 vs. vehicle, #p<0.05 vs. vehicle, n=10. Representative western blots are displayed below the graphs (LC stands for loading control)
Figure 4
Mechanisms by which free radical-induced lipid peroxidation contributes to intracellular Ca++ overload and calpain activation after TBI (see DISCUSSION for details).
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