The chemical properties and high density of depleted uranium (DU) render the metal well suited for military purposes. The US Army utilizes DU for tank armor and in munitions, deployed such weapons in the Gulf War I, and is currently deploying them in Iraq. However, knowledge of DU neurotoxicity and its treatment is lacking despite the apparent neurological basis of several components of Gulf War illness. For example, Gulf War veterans who retained fragments of DU shrapnel over several years have exhibited lowered performance on psychometric tests. Moreover, research in chronically exposed animals has reported alterations in nerve cell activity, suggesting DU-induced decreases in neuronal excitability. The applicant has further established the blood and brain levels of DU resulting from chronic exposure in rats, and has demonstrated the ability of such exposure to enhance glutamate neurotransmission in response to nerve stimulation and induce activation of one subtype of glutamate receptors. It has become apparent that a significant component of heavy metal neurotoxicity is attributable to enhanced oxidative stress -- increased production of reactive oxygen molecules and initiation of other mechanisms of cellular excitotoxicity. Uranium-induced oxidative stress has been observed in rat kidney and testis. Thus, drugs that possess antioxidant properties -- generally developed for other medical purposes -- offer novel approaches for the treatment of DU neurotoxicity. This application describes a proposal to investigate potential treatment options to address neurotoxicity from chronic DU exposure, which is thought to produce components of Gulf War illness. Older standards of medical practice dictated that difficult-to-retrieve metal fragments that were not affecting organ function be left in the wound. The proposed studies utilize a shrapnel wound-type model consisting of intramuscular DU implants to assess the ability of drug therapy to reverse the metal neurotoxicity. The bases of DU neurotoxicity are proposed to be cellular

metabolic dysfunction and the consequent increased production of reactive oxygen molecules, leading to increased synaptic glutamate concentrations in conjunction with glutamate receptor activation. Studies will identify various biochemical markers of metal-induced oxidative stress in brain regions important for cognitive function and, in combination with enhanced extracellular glutamate and receptor activation, will provide three components of DU neurotoxicity for assessment of therapeutic efficacy. It is hypothesized that long-term administration of a reactive oxygen molecule trapping agent and/or a glutamate receptor antagonist will reduce these neurotoxic signs. These studies will provide critical information on which to base new treatments for ill Gulf War veterans. Previous evidence suggests that the proposed therapeutic agents will reduce or eliminate this toxicity. At a minimum, testing the therapeutic agents will offer a treatment alternative to the organ damage that might be incurred in some cases by surgical removal of DU shrapnel. Since there is some experience with the use of the proposed agents in the treatment of other clinical conditions, administration of drug therapy could be instituted within a short period of time.