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Protective Mechanisms of Nitrone Antioxidants in Kanic Acid Induced Neurodegeneration

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Final rept. 1 Jun 1999-31 Dec 2003

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Our proposed research is focused on developing nitrone-based antioxidants as antidotes against chemical agents that induced excitatory neurotoxicity. We proposed to use kainic acid, an analog of the excitatory amino acid glutamate, to induce chronic neurological damage in adult rats. Exposure of rats to kainic acid KA, a non-NMDA type glutamate receptor agonist, induces recurrent delayed convulsive seizures and hippocampal neurodegeneration reminiscent of human epilepsy. In this study, the effects of KA were studied with respect to three separate signal transduction pathways likely to regulate inflammatory and apoptotic gene expression in the hippocampus. Immunohistochemical methods and electromobility gel shift assays EMSAs demonstrate the concerted activation of the NFkB pathway along with the activator-1 pathway AP-1 and the p38 mitogen-activated protein kinase pathway p38 MAPK. Activation of these three pathways occurred simultaneously with the expression of several proapoptotic biomolecules most notably TNF and the Fas antigen and simultaneously with the onset of convulsive seizures but prior to the initiation of neuronal apoptosis. Co-treatment with the experimental antioxidant and anti-inflammatory compound phenyl-N-tert-butylnitrone PBN resulted in a diminution of NFkB, AP-1 and p38 activation, suppressed cytokine and apoptotic gene expression, inhibited neuronal apoptosis, and diminished seizure activity. These 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.

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  • Medicine and Medical Research
  • Toxicology

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