DNA Damage In Cortex Research Articles

Neurobehavioral effects of vigabatrin and its ability to induce DNA damage in brain cells after acute treatment in rats.

Vigabatrin (VGB) is a drug indicated mostly for the treatment of spasms in childhood and West's syndrome patients. This drug inhibits irreversibly the enzyme GABA-transaminase (GABA-T), increasing GABA concentrations and enhancing GABAergic neurotransmission in the brain, which is known to induce behavioral changes. The aims of this study were to evaluate the effects of VGB in the short-term memory (STM), long-term memory (LTM), motivation, locomotion, and exploratory behavior tests and to detect deleterious or protective effects on DNA in target tissues of the drug. Male Wistar rats were treated with a single dose of VGB (100, 250, or 500mg/kg) or saline solution before the inhibitory avoidance and open-field tasks. DNA damage was evaluated using the alkaline comet assay in peripheral blood, cerebral cortex, and hippocampus after behavioral testing. There was no significant difference in the inhibitory avoidance task between the treated groups and the saline group. In all tested doses, VGB reduced the number of rearings in the open-field task. Besides, VGB 500mg/kg affected locomotion, though it was not able to induce any DNA damage. VGB did not affect STM and LTM, but the drug impaired the exploration and locomotion likely associated with its sedative effect. In addition, no DNA damage in cortex and hippocampus was detected after behavioral testing, when brain GABA levels are already increased.

DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology.

DNA damage has been proposed to underlie neuronal degeneration in aging and Alzheimer disease (AD). To determine the histological distribution of DNA damage, in situ end labeling (ISEL) was applied as a marker for DNA breaks on 4 differentially affected brain areas. Occipital cortex showed considerable variation between cortical layers and between patients. Temporal cortex displayed little ISEL-labeling in controls, and in AD, surprisingly. In the hippocampus, which is strongly affected in AD, many ISEL-positive nuclei and glialike cells were found in AD as compared with controls. The hypothalamic supraoptic and paraventricular nuclei showed little DNA-damage, whereas the nucleus basalis was often, but not always, labeled by ISEL. In contrast to others, no apoptotic morphology was observed, only necrotic morphology. Our results in relation to postmortem delay indicate that, area dependent, increased DNA vulnerability may occur in AD. Furthermore, the distribution of DNA damage in cortex differs from that of plaques and tangles, suggesting that these 3 phenomena are, in principle, independent. Whether the enhanced level of hippocampal DNA breaks in AD underlies, or rather is a consequence of, previous degenerative changes in this brain area remains to be established.

Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients

It has been hypothesized that Alzheimer's disease (AD) is caused by an accumulation of damage in DNA due to defective DNA-repair (21). Attempts to test this hypothesis by determining the activity of DNA-repair systems in nonneuronal cells from AD patients and controls so far provided conflicting results. An alternative approach is the direct comparison of DNA-damage levels in neuronal tissue of AD patients and controls. In the present study we assayed the level of DNA breaks and alkali-labile sites in cerebral cortex tissue samples from AD patients and controls obtained from rapid autopsies. Our data on 11 AD patients and 8 control subjects indicate an at least two-fold higher level of DNA damage in cortex of AD patients as compared to controls.