Accession Number : ADA436433


Title :   Protective Mechanisms of Nitrone Antioxidants in Kanic Acid Induced Neurodegeneration


Descriptive Note : Final rept. 1 Jun 1999-31 Dec 2003


Corporate Author : KENTUCKY UNIV LEXINGTON


Personal Author(s) : Bing, Guoying


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a436433.pdf


Report Date : Jan 2004


Pagination or Media Count : 121


Abstract : 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.


Descriptors :   *ANTIOXIDANTS , *NEUROTOXINS , *APOPTOSIS , *EPILEPSY , INHIBITION , CONVULSIVE DISORDERS , HIPPOCAMPUS


Subject Categories : Medicine and Medical Research
      Toxicology


Distribution Statement : APPROVED FOR PUBLIC RELEASE