Neurotoxicology
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We previously found evidence of reduced gray and white matter volume in Gulf War (GW) veterans with predicted low-level exposure to sarin (GB) and cyclosarin (GF). Because loss of white matter tissue integrity has been linked to both gray and white matter atrophy, the current study sought to test the hypothesis that GW veterans with predicted GB/GF exposure have evidence of disrupted white matter microstructural integrity. ⋯ The finding that increased axial diffusivity in a region of the brain that contains descending corticospinal fibers was associated with better psychomotor function and the lack of significant neurobehavioral deficits in veterans with predicted GB/GF exposure hint at the possibility that the widespread increases in axial diffusivity that we observed in GW veterans with predicted GB/GF exposure relative to unexposed controls may reflect white matter reorganization after brain injury (i.e., exposure to GB/GF).
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N-acetyl-aspartyl-glutamate (NAAG) is the most abundant neuropeptide in the mammalian brain. In a variety of animal models of brain injury, the administration of NAAG-related compounds, or inhibitors of glutamate carboxypeptidases (GCPs; the enzymes that hydrolyze NAAG), were shown to be neuroprotective. This study determined the impact of the administration of three NAAG-related compounds, NAAG, β-NAAG (a NAAG homologue resistant to degradation), and 2-phosphonomethyl pentanedioic acid (2-PMPA; an inhibitor of GCP enzymes), on the neuropathology that develops following exposure to the nerve agent, soman. ⋯ Histochemical study indicated there was a dramatic increase in Fluoro-Jade C (FJC) staining, indicative of neuron cell death, 24 h after soman exposure. However, in the amygdala and in the entorhinal and piriform limbic cortex, which sustained severe neuropathology following soman intoxication, single or combined injections of NAAG compounds and 2-PMPA significantly reduced the number of FJC-positive cells, and effect size estimates suggest that in some brain regions the treatments were effective. The findings suggest that NAAG neurotransmission in the central nervous system is significantly altered by soman exposure, and that the administration of NAAG-related compounds and 2-PMPA reduces neuron cell death in brain regions that sustain severe damage.