Amelioration of Mitochondrial Function by a Novel Antioxidant U-10103 3E Following Traumatic Brain Injury in Rats

Abstract

In the present study, a severe traumatic brain injury (TBI) was produced over the right parietal cortex of rats using the controlled cortical impact injury (CCII) model. TBI perturbed calcium homeostasis and impaired electron transfer and energy coupling activities of forebrain mitochondria isolated from injured hemispheres with a maximal injury at 12-72 h. Efficacy of the blood-brain barrier penetrating antioxidant U-101033E on TBI-induced mitochondrial impairment was evaluated. In the dose-response experiment, two i.v. boluses (vehicle or 1-10 mg/kg of U-101033E) were administered at 5 min and 2h post-TBI. Forebrain mitochondria from each hemisphere were examined at 12 h post-injury. With respect to forebrain mitochondrial dysfunction, the drug showed a bell-shaped dose-response curve with an optimal dose of 3 mg/kg (n = 5, p < 0.05 vs. vehicle). In the time-course experiment, two i.v. boluses of 3 mg U-101033E/kg (the optimal dose) were given at 5 min and 2 h post-injury and forebrain mitochondria were examined at 6 h-14 days post-injury. U-101033E significantly restored electron transfer, energy coupling capacity, and Ca2+ transport capacity during 6 h to 14 days post-injury. Our data indicate that the antioxidant U-101033E administered post-injury at proper dosage can effectively restore TBI-induced mitochondrial dysfunction and support the contention that oxidative stress plays an important role in the pathogenesis of TBI.

The protective role of cellular glutathione peroxidase against trauma-induced mitochondrial dysfunction in the mouse brain

“…21,[54][55][56][57][58][59][60][61][62][63] However, it should be noted that treatment of animals with antioxidants can effectively attenuate the increased content of mitochondrion-associated calcium and mitochondrial dysfunction. 30,31 These results and this study suggest that an increase in oxidative stress may be prerequisite for the increased content of intracellular calcium in neurons of mice after TBI. This hypothesis does not entirely agree with the current concept in excitatory amino acids-induced neuronal injury, that calcium influx into neurons after excessive release of glutamate is mediated through activation of N-methyl-D-aspartate and calcium-permeable AMPA receptors and through voltage-gated calcium channels, and may be independent from the increased oxidative stress.…”

“…24 This hypothesis is supported by the findings that increased levels of ROS including superoxide anion radical and hydroxyl radical and oxidative metabolites of lipid and DNA are found in injured brain tissues compared with those of control subjects 13,[25][26][27][28][29] and that treatment of rats with antioxidant U-101033E or N-acetylcysteine alleviates brain injury. 30,31 Although these studies have clearly demonstrated the pathogenic role of ROS in TBI, the function of each antioxidant enzyme in preventing TBI is unclear. We hypothesize that if an antioxidant enzyme plays a crucial role in cellular protection against TBI, mice overexpressing this enzyme will exhibit a resistant phenotype and mice deficient in this enzyme a sensitive phenotype.…”

Mice Lacking Catalase Develop Normally but Show Differential Sensitivity to Oxidant Tissue Injury

“…Alternatively, the overloaded calcium may cause an opening of the mitochondrial permeability transition pore, resulting in uncoupling of the electron transport chain. Nonetheless, treatment of animals with antioxidants attenuates the increased content of mitochondrion-associated calcium and mitochondrial dysfunction (65,66), suggesting that calcium overloading in traumainjured brain is secondary to the increased oxidative stress.…”

Mitochondrial Participation in Ischemic and Traumatic Neural Cell Death

“…Cyclosporin A was also shown to be neuroprotective in another model of TBI, where it additionally reduced the appearance of mitochondrial swelling, as analyzed by electron microscopic observations of fixed brain tissue (Okonkwo and Povlishock, 1999). Others have provided evidence for protection against brain mitochondrial respiratory injury through treatment of animals with Ca2+ channel blockers and antioxidants (Verweij et al, 1997;Xiong et al, 1997bXiong et al, , 1998Xiong et al, , 1999. These correlations of pharmacologie protection against mitochondrial injury with improved outcomes clearly support the need for more extensive research into mitochondria as subcellular targets for neuroprotective interventions.…”