Novel Pharmacological Approaches for Treatment of Neurotoxicity Induced by Chronic Exposure to Depleted Uranium.

摘要

The chemical properties and high density of depleted uranium (DU) render the metal well suited for military purposes. The U. S. Army utilizes DU for tank armor and in munitions, deployed such weapons in the first Gulf War, and is currently deploying them in Afghanistan. However, knowledge of DU neurotoxicity and its treatment is lacking despite reports of exposed cohorts exhibiting neurocognitive dysfunction (1). Research in chronically exposed rats has reported alterations in hippocampal synaptic transmission, suggesting DU- induced decreases in neuronal excitability (2). This project examined potential treatment options to address neurotoxicity from chronic DU exposure. On the basis of previous observations the underlying effects of DU neurotoxicity were proposed to be cellular oxidative stress and the consequent increased production of reactive oxygen species, leading to decreased glutamate uptake and increased synaptic glutamate concentrations in conjunction with NMDA receptor up-regulation. Uranium-induced oxidative stress has previously been reported in rat kidney, testis, and lung (3-4). Studies were designed to identify various biochemical markers of metalinduced oxidative stress in CNS tissue, and in combination with enhanced extracellular glutamate and NMDA receptor activity would provide three components of DU neurotoxicity for assessment of therapeutic efficacy. It was hypothesized that long-term administration of an anti-excitotoxic agent and/or an NMDA receptor antagonist would reduce DU neurotoxicity. It was hoped that these studies would provide critical information on which to base new treatments for exposed Gulf War veterans.