Pharmacological Inhibition of Lipid Peroxidative Damage by the 21-aminosteroid U-74389G Improves Cortical Mitochondrial Function Following Traumatic Brain Injury in Young Adult Male Rats

The 21-aminosteroid ("lazaroid") U-74389G (U74), an inhibitor of lipid peroxidation (LP), was used to protect mitochondrial function following TBI in young adult male rats. The animals received a severe (2.2 mm) controlled cortical impact-TBI. U74 was administered intravenous at 15 min and 2 h post injury (hpi) followed by intraperitoneal dose at 8 hpi at the following doses (mg/kg): 0.3 (IV) + 1 (IP), 1 + 3, 3 + 10, 10 + 30. Total cortical mitochondria were isolated at 72 hpi and respiratory rates were measured. Mitochondrial 4-HNE and acrolein were evaluated as indicators of LP-mediated oxidative damage. At 72 h post-TBI injured animals had significantly lower mitochondrial respiration rates compared to sham. Administration of U74 at the 1 mg/kg dosing paradigm significantly improved mitochondrial respiration rates for States II, III, V(II) and RCR compared to vehicle-treated animals. At 72 h post-TBI injured animals administration of U74 also reduced reactive aldehydes levels compared to vehicle-treated animals. The aim of this study was to explore the hypothesis that interrupting secondary oxidative damage via acute pharmacological inhibition of LP by U74 following a CCI-TBI would provide mitochondrial neuroprotective effects in a dose-dependent manner. We found acute administration of U74 to injured rats resulted in improved mitochondrial function and lowered the levels of reactive aldehydes in the mitochondria. These results establish not only the most effective dose of U74 treatment to attenuate LP-mediated oxidative damage, but also set the foundation for further studies to explore additional neuroprotective effects following TBI.