This (Oklahoma Medical Research Foundation) research focuses on developing nitrone-based antioxidants as antidotes against chemical agents that induce excitatory neurotoxicity. It is proposed to use kainic acid, an analog of the excitatory amino acid glutamate, to induce chronic neurological damage in adult rats. This model has been widely used as a model for studying human temporal lobe epilepsy. The delayed neuronal degeneration induced by kainic acid resembles CNS neuronal injury, repair, and plasticity.
Preliminary observations show that nitrone antioxidants -- free radical trapping compounds -- protect rats from kainic-acid-induced death. It is found that cotreatment with the experimental antioxidant phenyl-N- tert-butylnitrone (PBN) results in: diminution of NrkB, AP-l, and p38 activation; suppressed cytokine and apoptotic gene expression; inhibited neuronal apoptosis; and diminished seizure activity. The data suggest that pharmacological antagonism of multiple signal transduction pathways is achievable in the brain, and that inhibition of these processes may prevent a cascade of gene-inductive events leading to neuronal apoptosis. The results clarify the molecular basis for KA-induced seizure activity, and may indicate a novel therapeutic strategy for certain chronic neurodegenerative disorders.
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