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

Abstract

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 (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.

Antioxidant therapies in traumatic brain and spinal cord injury

“…More recently U-83836E has also been shown to inhibit calpain-mediated cytoskeletal degradation in the same model (Fig. 1) signifying the intricate relationship between post-traumatic LP, disruptions in neuronal Ca 2+ homeostasis and calpain-mediated cytoskeletal damage [86]. In this regard, U-83836E is able to inhibit an early event in a series of linked secondary injury pathways, thereby providing neuroprotection at multiple biochemical levels (See Fig.…”

Therapy Development for Diffuse Axonal Injury

“…In particular, activated calpain has been well studied with regard to proteolysis of subaxolemmal spectrin, with the resultant breakdown products detected in damaged axons and in the CSF. 38,41,42,133,134,165,168,[170][171][172] Less well known is the role of calpain on ankyrin proteolysis, which may lead to disordered sodium channel arrangement at the nodes of Ranvier, and its altered binding to neurofascin, which may contribute to axolemmal instability. 173 Several in vivo studies have examined various axonal protective strategies targeting calcium-mediated responses by either direct or indirect means.…”

Antioxidant therapies in traumatic brain injury: a review

“…Its structure enables the dual functionality of LP inhibition and scavenging LOO•, thereby making it much more effective than the endogenous scavenger vitamin E44. U-83836E treatment can attenuate post-traumatic LP in cerebral cortical tissue or mithochondria together with a preservation of aerobic respiratory function and Ca++-buffering capacity (45). More recently U-83836E has also been shown to inhibit calpain-mediated cytoskeletal degradation signifying the intricate relationship between post-traumatic LP, disruptions in neuronal Ca2+ homeostasis and calpain-mediated cytoskeletal damage (12).…”