DNA Damages Induced Neuronal Death
Abstract
Neuronal cultures prepared from the cerebellum, cortex, or midbrain of wild-type, DNA repair-overexpressing (i.e., O(exp 6)-methylguanine methyltransferase, MGMT(+)) or DNA repair-deficient (i.e., XPA(-/-)) mice were examined for sensitivity to nitrogen mustard (HN2) or the related alkylating agent methylazoxymethanol (MAM). The MGMT(+) studies examined whether the neurotoxicity of HN2 and MAM could be blocked by overexpressing MGMT in cerebellar neurons. As proposed, neuronal survival, membrane integrity and mitochondrial function were essentially maintained in cerebellar MGMT(+) neurons treated with MAM, but not after HN2 treatment. These findings suggest that MGMT protects neurons from MAM-induced cytotoxicity, but not from HN2-induced cytotoxicity. In separate studies, cerebellar neurons from mice defective in the nucleotide excision repair (NER) protein XPA, a key protein that repairs x-links and UV DNA damage, were examined for their sensitivity to HN2 and MAM. The increased sensitivity of NER-deficient neurons to HN2 and not to MAM suggests that the inefficient removal of x-links plays an important role in mustard-induced neurotoxicity. Additional studies are underway using neuronal and astrocyte cell cultures of other DNA repair-deficient mice to determine if mustard-induced neurotoxicity is dependent upon the inefficient removal of a specific mustard-induced DNA adduct (i.e., N(exp 7)-alkylguanine vs. x-links).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2000
- Accession Number
- ADA384821
Entities
People
- Glen Kisby
Organizations
- Oregon Health & Science University