Oxidative Stress Following Traumatic Brain Injury in Aging

Each year a higher percentage of individuals age 75+ die from traumatic brain injury (TBI) than any other age group making head trauma a prominent cause of death in elderly individuals in the US. Elderly trauma victims demonstrate decreased survival rates compared with younger victims with a similar degree of injury and are twice as likely to die of their injuries. This disparity in injury outcome may be due to the effects of aging on the body's ability to respond to injury. The results ofTBI are commonly separated into the primary injury which involves a physical disruption of vascular and neuronal tissue, and a secondary injury in which neurons originally spared from injury undergo degeneration. Current evidence implicates oxidative stress as a significant cause of secondary neuronal damage following TBI. However, there are few studies of levels of oxidative stress or the enzymes that protect against free radical attack as a function of age or time post injury. This proposal hypothesizes that age-dependent alterations in the response of antioxidant enzyme capacities contribute to increased levels of lipid peroxidation and the generation of neurotoxic aldehydic products of lipid peroxidation which increase neuronal degeneration and lead to increased mortality rates observed in aged TBI patients. In ipsilateral (IPS) cortex, preliminary data show a significant increase in levels of 4-hydroxynonenal (RNE), a neurotoxic marker of lipid peroxidation, in all age groups compared with age-matched sham animals. The cortex of injured animals also shows significant reductions in enzymes responsible for protection against oxidative stress or against HNE including Cu/Zn superoxide dismutase (Cu/Zn SOD), manganese SOD (Mn SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R) and glutathione transferase (GST) in middle-aged and aged rats compared with young rats. Preliminary analysis of IPS cortex demonstrates no significant differences between levels of HNE or protective enzymes between middle-aged and aged rats, which suggests a ceiling effect due to the severity of injury. In hippocampus, preliminary data show an age-dependent increase in levels ofRNE and an age-dependent decrease in all antioxidant enzymes studied except thioredoxin reductase (TR). Preliminary studies ofIPS hippocampus also demonstrate a pronounced loss ofthioredoxin in middleaged and aged rats subjected to TBI. The proposed studies will demonstrate that aging leads to a decrease in protective mechanisms in both the cortex and hippocampus and an increase in markers of DNA oxidation and neurotoxic markers oflipid peroxidation, and that early treatment with EUK-134, a catalase/SOD mimetic, following TBI will lead to increased recovery from injury. The specific aims of this project are: 1) to quantify levels ofHNE and acrolein, neurotoxic markers of lipid peroxidation at various times after TBI in young, middle-aged and aged Fisher-344 rats as a model ofTBI in aged humans and to quantify the degree oflesion volume and hippocampal cell counts 7 days post injury; 2) to quantify and correlate levels of antioxidant enzymes including Cu/Zn SOD, Mn SOD, GSH-Px, GSSG-R, GST and TR; and 3) to evaluate the role of early treatment with EUK-134 which should demonstrate potent antioxidant capabilities and protect aged animals against TBI. .