DNA Damage Induced Neuronal Death
Annual rept. 1 Sep 2001-1 Sep 2002
OREGON HEALTH SCIENCES UNIV PORTLAND
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Neuronal and astrocyte cell cultures from the cerebellum and fibroblasts and epithelial cells from the skin and kidney respectively of DNA repair mutant mice were examined for the acute and delayed toxicity to nitrogen mustard HN2 or the related alkylating agent methylazoxymethanol MAM. Cerebellar neurons from DNA repair mutant mice i.e., XPAsup --, MGMTsup -- were more sensitive to HN2 and MAM than comparably treated wild type or AAGsup -- neurons. Cerebellar neurons from MGMT mice were protected from the acute toxicity of both MAM and HN2. A similar pattern of sensitivity was observed for long-term HN2- and MAM-treated cerebellar neurons or fibroblasts and epithelial cell lines from DNA repair deficient i.e., MGMTsup --, AAGsup -- mice. In comparison to wild type and DNA mutant i.e., MGMTsup --, AAGsup -- mice, the loss of cerebellar neurons, degeneration and altered dopaminergic neurons were especially evident in the brains of MGMTsup -- mice administered MAM. These findings are consistent with HN2 and MAM selectively targeting neural and non-neural cells in vivo via a mechanism involving DNA damage. In vivo studies are currently underway with DNA repair-deficient mice to further examine the relationship between DNA damage and in vivo neurotoxicity of MAM and HN2.
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