Reactive oxygen species-induced oxidative damage remains an extensively validated secondary injury mechanism in
traumatic brain injury (TBI) as demonstrated by the efficacy of various pharmacological
antioxidants agents in decreasing post-traumatic
free radical-induced lipid peroxidation (LP) and
protein oxidative damage in preclinical TBI models. Based upon strong preclinical efficacy results, two
antioxidant agents, the
superoxide radical scavenger
polyethylene glycol-conjugated
superoxide dismutase (
PEG-SOD) and the 21-aminosteroid LP inhibitor
tirilazad, which inhibits lipid peroxidation, (LP) were evaluated in large phase III trials in moderately- and severely-injured TBI patients. Both failed to improve 6 month survival and neurological recovery. However, in the case of
tirilazad, a post hoc analysis revealed that the
drug significantly improved survival of male TBI patients who exhibited
traumatic subarachnoid hemorrhage (tSAH) that occurs in half of severe TBIs. In addition to reviewing the clinical trial results with
PEG-SOD and
tirilazad, newer
antioxidant approaches which appear to improve neuroprotective efficacy and provide a longer therapeutic window in rodent TBI models will be presented. The first approach involves pharmacological enhancement of the multi-mechanistic Nrf2-antioxidant response element (ARE) pathway. The second involves scavenging of the neurotoxic LP-derived carbonyl compounds
4-hydroxynonenal (4-HNE) and
acrolein which are highly damaging to neural
protein and stimulate additional
free radical generation. A third approach combines mechanistically complimentary
antioxidants to interrupt post-TBI oxidative neurodegeneration at multiple points in the secondary injury cascade. These newer strategies appear to decrease variability in the
neuroprotective effect which should improve the feasibility of achieving successful translation of
antioxidant therapy to TBI patients.