DNA Damages Induced Neuronal Death
Abstract
Neuronal and astrocyte cell cultures prepared from the cerebellum, cortex, or midbrain of wild-type or DNA repair-deficient (i.e., MGMT(sup -/-), AAG(sup -/-), XPA(sup -/-) mice were examined for the acute toxicity to nitrogen mustard (HN2) or the related alkylating agent methylazoxymethanol (MAM). Cerebellar neurons were more sensitive to MAM and HN2 than astrocytes or neurons from other brain regions (i.e., cortex and midbrain). This sensitivity to MAM and HN2 was accompanied by markers of apoptosis and DNA damage (i.e., single-strand breaks). In comparably treated cultures from DNA repair-deficient mice, cell survival was preserved in AAG(sup -/-) neurons, but reduced in MGMT(sup -/-) and XPA(sup -/-) neurons treated with HN2 or MAM. Unexpectedly, neuronal survival was significantly reduced in MGMT(sup -/-) cerebellar neurons treated with HN2. Similar results were also obtained for comparably treated fibroblast cell lines from all three DNA repair-deficient mice. However, the long-term survival of fibroblasts were only reduced in MGMT(sup -/-) and XPA(sup -/-) fibroblasts treated with HN2 or MAM. Loss of cerebellar neurons, degeneration and DNA damage were also observed in wild type mice administered MAM. In vitro and in vivo studies are currently underway with DNA repair-deficient mice to further examine the relationship between DNA damage and the delayed neurotoxicity of MAM and HN2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2001
- Accession Number
- ADA398071
Entities
People
- Glen Kisby
Organizations
- Oregon Health & Science University