Brain Damage Caused by Chemical Warfare Agents: Are Free Radicals a Final Common Pathway

摘要

The problem investigated was to test the hypothesis that neurotoxins initiate a cascade of events that converge on the redox mechanisms common to brain injury. Neurotoxins (e.g., soman, kainic acid, cyanide, etc.) initiate biochemical changes in brain that lead either to marked hyperactivity (i.e., soman- or kainic acid-induced seizures) or hypoactivity (i.e., cyanide-induced comatose) of brain regions. In both situations, protective mechanisms are activated to conserve energy, but eventually excitotoxic driven events ensue leading to an influx of calcium (i.e., calcium stress) and water movements (i.e. , osmotic stress). These stresses converge on the brain redox systems. Task 1 dealt with detection of biomarkers for free radicals in cerebral extracellular fluid via microdialysis and in regional brain tissues. Both cyanide and soman cause marked changes in ascorbate and urate. Kainic acid-induced seizures increase nitric oxide formation. Soman increased 'catalytic iron' and decreased tissue glutathione. Task 2 dealt with detection of tissue biomarkers of free radical responses by gene expression studies. Kainic acid, a surrogate seizuregenic compound, changes metallothionein-1, heme oxygenase-1, c-fos, heat shock protein-70 and interleukin-1 gene expression in brain. Soman caused marked changes in metallothionein-1 and heme oxygenase-1. Clearly, the redox state is important in neurotoxin-induced brain damage.