Transcripts of damaged genes in the brain during cerebral oxidative stress

Abstract

Recent studies using ischemia/reperfusion models of brain injury suggest that there is a period of time during which the formation of oxidative DNA lesions (ODLs) exceeds removal. This interval is a window of opportunity in which to study the effect of gene damage on gene expression in the brain, because the presence of excessive ODLs mimics a deficiency in gene repair, which has been shown to be associated with neurological disorders. Evidence from studies using similar models indicates that expression of faulty transcripts from ODL-infested genes and non-sense mutation in repaired genes occur before the process of cell death. Preventing the formation of ODLs and enhancing ODL repair are shown to increase the expression of intact transcripts and attenuate cell death. Understanding this mechanism could lead to the development of therapeutic techniques (physiologic, pharmacological, and/or genomic) that can enhance recovery.

Fig. 1

Presence of ODLs in three nuclear genes of the brain after FCIR. [Combined data from Cui et al., 1999b; Moore et al., 2002.]

Fig. 2

Hypothesis of ODLs causing faulty gene transcription and the failure to activate late effector genes. One particular pathway presented here is the activation of neurotrophin by the Fos/AP-1 complex, products of the c-jun and c-fos supergene families. Damage to the c-fos gene can be reduced via gene repair or inhibitors/scavengers that reduce reactive oxygen species (Liu et al., 2001). NTGs, neurotrophin genes; FGF, fibroblast growth factor; PARP, poly(ADP-ribose) polymerase.

Fig. 3

Repair activities are further enhanced in the presence of nNOS inhibition. Forebrain ischemia/reperfusion-induced mouse 8-hydroxy-2′-deoxyguanosine (oh8dG) glycosylase activities that remove oh8dG in brain extracts in four groups of animals were measured by the excision of oh8dG (X in 5′-³²P-CATCATGGTCXTGGTTTGGGCA-3′; see Lin et al., 2000).