Transient Global Ischemia Triggers Expression of the DNA Damage-Inducible Gene GADD45 in the Rat Brain

Abstract

Using in situ hybridization, Northern blot analysis, Western blot analysis, and immunocytochemistry, mRNA and protein expression of the novel DNA damage-inducible gene GADD45 was examined in the rat brain at 0.5, 2, 4, 8, 16, 24, 48, and 72 hours after 15 minutes of transient global ischemia. Transient ischemia produced by the four-vessel occlusion method resulted in DNA double-strand breaks and delayed neuronal cell death in vulnerable neurons of the hippocampal CA1 sector, the hilus, dorsal caudate-putamen, and thalamus, as shown by in situ DNA nick end-labeling and histologic staining. GADD45 mRNA was transiently increased in less-vulnerable regions such as the parietal cortex (up to 8 hours after ischemia) and dentate granule cells (up to 24 hours after ischemia) but was persistently increased in vulnerable neurons such as CA1 pyramidal neurons (up to 48 hours). GADD45 immunoreactivity was increased in both vulnerable and less-vulnerable regions at earlier reperfusion periods (4 to 16 hours), but thereafter immunoreactivity was decreased below control levels in most vulnerable regions before delayed cell death and DNA double-strand breaks. At 72 hours after transient ischemia, a moderate increase in GADD45 immunoreactivity was still detectable in some CA3 neurons and in a few surviving neurons in the CA1 region. Double staining performed at 16 to 72 hours after ischemia revealed that GADD45 immunoreactivity was persistently increased in neurons that did not develop DNA damage. Because GADD45 protein may participate in the DNA excision repair process and because it has been shown that this protein is also overexpressed in neurons that survive focal ischemia and kainate-induced epileptic seizures, the results reported here support the hypothesis that GADD45 could have a protective role in neuronal injury.

Growth Arrest and DNA-Damage-Inducible, Beta (GADD45b)-Mediated DNA Demethylation in Major Psychosis

“…In addition, many of the IPL functions, such as sensory integration, body image, concept of self, visuospatial abilities, and executive functions have been found to be disturbed in SZ (Jimenez et al, 2010;Torrey, 2007;Naghavi and Nyberg, 2005). Also, GADD45 proteins have been shown to be highly regulated in this region of the cortex (Chen et al, 1998;Zhu et al, 1997). Subsequently, we sought to confirm that gene expression abnormalities are not limited to this region using prefrontal cortical sections from the Harvard Brain Tissue Resource Center.…”

Oxidative Stress, Mitochondrial Dysfunction, and Stress Signaling in Alzheimers Disease

“…One of the proteins regulated by NF-κB is Gadd45. Neuronal expression of Gadd45a has been noted to increase in the brain following ischaemia [190][191][192][193], cortical contusion [194], excitotoxic lesions [195] and seizures [196,197]. These findings have led to the suggestion that this gene may have a protective role after neuronal injury [190,191,198].…”

Differential proliferative response in the postischemic hippocampus, temporal cortex, and olfactory bulb of young adult macaque monkeys

“…Gadd45 was selected because its increased expression was demonstrated previously in a rodent model of global isch-emia (Chen et al, 1998). Furthermore, it is not a direct component of the DNA replication apparatus, as are some other DNA repair markers.…”