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Comparison of Novel and Known Neuroprotectants for Treating Exposure to Different Types of Toxins

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Final rept. 16 Aug 1999-15 Aug 2004

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Studies using cultured brain slices have found that compensatory signals are activated in response to different types of excitotoxicityseizures related to environmental toxin or military threat agent exposure. Soman, an irreversible anticholinesterase and devastating weapon of mass destruction, produces convulsions, memory impairment, and cell loss in the brain, especially in the hippocampus. Soman-induced accumulation of acetylcholine initiates mechanisms responsible for the development of incapacitating seizures. However, another excitatory neurotransmitter, glutamate, also has been linked to the toxic action of the chemical agent We found that after repeated exposures to sub-toxic levels of soman, long-term hippocampal slice cultures from rat exhibit enhanced vulnerability to brief excitotoxic episodes of glutamate receptor over-stimulation. In particular, the hippocampal tissue became sensitive to cytoskeletal damage and synaptic decline in response to secondary pathogenic events. Thus, seemingly innocuous soman exposures leave the brain vulnerable to excitotoxic insults that are implicated in traumatic brain injury and stroke. The findings also suggest that asymptomatic exposures to soman can lead to hippocampal damage and that early indicators of low-level soman contact are critical for the prevention of subsequent brain injury. Studies with receptor modulators are helping to identify key signal transduction pathways that lead to neuroprotection vs. those that enhance neuronal vulnerability. Accordingly, a neuroprotectant that acts against excitotoxicity through the MAP kinase pathway eliminates soman-induced neuronal vulnerability.

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  • Medicine and Medical Research
  • Stress Physiology
  • Toxicology

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