Protective Mechanisms of Nitrone Antioxidants in Kainic Acid Induced Neurodegeneration

摘要

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. 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. We have found that nitrone antioxidants, free radical trapping compounds, protected rats from kainic acid induced death and that co-treatment with the experimental antioxidant, phenyl-N-tert-butylnitrone (PBN) resulted in a diminution of NFkB, AP-l, 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. More recently, We have characterized other nitrone antioxidants, 2- hydroxy PBN, 3-hydroxy PBN, 4-hydroxy PBN, have similar effects. These results clarify the molecular basis for KA-induced seizure activity and may indicate a novel therapeutic strategy for certain chronic neurodegenerative disorders.