390 - Extracellular Superoxide Dismutase as a Therapeutic Target in a Mouse Model of Gulf War Illness

Abstract

More than twenty five years after the end of the 1900-1991 Gulf War, a substantial contingent of veterans still suffer from a number of health problems such as chronic fatigue, muscle and joint pain, cognitive deficits, etc. – this constellation of symptoms is collectively termed Gulf War Illness. The etiology of Gulf War Illness remains elusive, yet likely involves exposure to various chemicals as well as physical and psychological stresses unique to the Gulf War theatre. We adapted a mouse model of Gulf War Illness by exposing mice to Gulf War-related chemicals in addition to immobilization stress and assessed their cognitive functions along with pain susceptibilities. The mouse model recapitulated several aspects of the human illness, namely deficits in working spatial memory and recognition memory, along with heightened pain sensitization—precursor to chronic pain, impaired descending inhibition of pain, and increased tonic pain. Neuropathological changes, including the presence of neuroinflammation and increased oxidative stress, were found in brain tissues long after the completion of Gulf War chemical exposure. Coinciding with these chronic conditions was a reduction in the perineuronal net encapsulating inhibitory neurons, suggesting an imbalance in the excitation and inhibition of neuronal signal transmission. To assess whether enhanced antioxidant capacity can suppress the aforementioned neuroinflammation and oxidative stress, and ultimately counter the symptoms of Gulf War Illness, transgenic mice overexpressing extracellular superoxide dismutase in neurons (EC-SOD mice) were utilized. These mice were also exposed to Gulf War-related chemicals and immobilization stress, after which cognitive functions along with pain susceptibilities were assessed. The negative impacts of Gulf War, including neuropathological changes, cognitive deficits, and pain susceptibilities were largely diminished in these EC-SOD mice, suggesting the benefit of antioxidants in improving symptoms of Gulf War Illness.