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Oxidative Damage to the c‐ fos Gene and Reduction of Its Transcription After Focal Cerebral Ischemia
Author(s) -
Cui Jiankun,
Holmes Eric H.,
Liu Philip K.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0731164.x
Subject(s) - transcription (linguistics) , gene expression , microbiology and biotechnology , ischemia , messenger rna , gene , in situ hybridization , cerebral cortex , biology , chemistry , endocrinology , medicine , biochemistry , philosophy , linguistics
: We investigated oxidative damage to the c‐ fos gene and to its transcription in the brain of Long‐Evans rats using a transient focal cerebral ischemia and reperfusion (FCIR) model. We observed a significant ( p < 0.001) increase in the immunoreactivity to 8‐hydroxy‐2′‐guanine (oh8G) and its deoxy form (oh8dG) in the ischemic cortex at 0‐30 min of reperfusion in all 27 animals treated with 15‐90 min of ischemia. Treatment with a neuronal nitric oxide synthase (nNOS) inhibitor, 3‐bromo‐7‐nitroindazole (60 mg/kg, i.p.), abolished the majority but not all of the oh8G/oh8dG immunoreactivity. Treatment with RNase A reduced the oh8G immunoreactivity, suggesting that RNA may be targeted. This observation was further supported by decreased levels of mRNA transcripts of the c‐ fos and actin genes in the ischemic core within 30 min of reperfusion using in situ hybridization. The reduction in mRNA transcription occurred at a time when nuclear gene damage, detected as sensitive sites to Escherichia coli Fpg protein in the transcribed strand of the c‐ fos gene, was increased 13‐fold ( p < 0.01). Our results suggest that inhibiting nNOS partially attenuates FCIR‐induced oxidative damage and that nNOS or other mechanisms induce nuclear gene damage that interferes with gene transcription in the brain.