Delayed neuromotor recovery and increased memory acquisition dysfunction following experimental brain trauma in mice lacking the DNA repair gene XPA.

OBJECT: This study investigates the outcome after traumatic brain injury (TBI) in mice lacking the essential DNA repair gene xeroderma pigmentosum group A (XPA). As damage to DNA has been implicated in neuronal cell death in various models, the authors sought to elucidate whether the absence of an essential DNA repair factor would affect the outcome of TBI in an experimental setting. METHODS: Thirty-seven adult mice of either wild-type (n = 18) or XPA-deficient ("knock-out" [n = 19]) genotype were subjected to controlled cortical impact experimental brain trauma, which produced a focal brain injury. Sham-injured mice of both genotypes were used as controls (9 in each group). The mice were subjected to neurobehavoral tests evaluating learning/acquisition (Morris water maze) and motor dysfunction (Rotarod and composite neuroscore test), pre- and postinjury up to 4 weeks. The mice were killed after 1 or 4 weeks, and cortical lesion volume, as well as hippocampal and thalamic cell loss, was evaluated. Hippocampal staining with doublecortin antibody was used to evaluate neurogenesis after the insult. RESULTS: Brain-injured XPA(-/-) mice exhibited delayed recovery from impairment in neurological motor function, as well as pronounced cognitive dysfunction in a spatial learning task (Morris water maze), compared with injured XPA(+/+) mice (p < 0.05). No differences in cortical lesion volume, hippocampal damage, or thalamic cell loss were detected between XPA(+/+) and XPA(-/-) mice after brain injury. Also, no difference in the number of cells stained with doublecortin in the hippocampus was detected. CONCLUSIONS: The authors' results suggest that lack of the DNA repair factor XPA may delay neurobehavioral recovery after TBI, although they do not support the notion that this DNA repair deficiency results in increased cell or tissue death in the posttraumatic brain.

Green tea polyphenols prevent UV-induced immunosuppression by rapid repair of DNA damage and enhancement of nucleotide excision repair genes.

UV radiation-induced immunosuppression has been implicated in the development of skin cancers. Green tea polyphenols (GTP) in drinking water prevent photocarcinogenesis in the skin of mice. We studied whether GTPs in drinking water (0.1-0.5%, w/v) prevent UV-induced immunosuppression and (if so) potential mechanisms of this effect in mice. GTPs (0.2% and 0.5%, w/v) reduced UV-induced suppression of contact hypersensitivity (CHS) in response to a contact sensitizer in local (58-62% reductions; P < 0.001) and systemic (51-55% reductions; P < 0.005) models of CHS. Compared with untreated mice, GTP-treated mice (0.2%, w/v) had a reduced number of cyclobutane pyrimidine dimer-positive (CPD(+)) cells (59%; P < 0.001) in the skin, showing faster repair of UV-induced DNA damage, and had a reduced (2-fold) migration of CPD(+) cells from the skin to draining lymph nodes, which was associated with elevated levels of nucleotide excision repair (NER) genes. GTPs did not prevent UV-induced immunosuppression in NER-deficient mice but significantly prevented it in NER-proficient mice (P < 0.001); immunohistochemical analysis of CPD(+) cells indicated that GTPs reduced the numbers of UV-induced CPD(+) cells in NER-proficient mice (P < 0.001) but not in NER-deficient mice. Southwestern dot-blot analysis revealed that GTPs repaired UV-induced CPDs in xeroderma pigmentosum complementation group A (XPA)-proficient cells of a healthy person but did not in XPA-deficient cells obtained from XPA patients, indicating that a NER mechanism is involved in DNA repair. This study is the first to show a novel NER mechanism by which drinking GTPs prevents UV-induced immunosuppression and that inhibiting UV-induced immunosuppression may underlie the chemopreventive activity of GTPs against photocarcinogenesis.

Polypodium leucotomos extract decreases UV-induced Cox-2 expression and inflammation, enhances DNA repair, and decreases mutagenesis in hairless mice.

UV-irradiated skin and UV-induced tumors overexpress the inducible isoform of cyclooxygenase-2 (Cox-2), and Cox-2 inhibition reduces photocarcinogenesis. To evaluate photoprotective effects of Polypodium leucotomos extract (PL), hairless Xpc(+/-) mice were fed for 10 days with PL (300 mg/kg) or vehicle then UV-irradiated, once. By 24 hours, UV-induced Cox-2 levels were increased in vehicle-fed and PL-fed mice, whereas by 48 and 72 hours, Cox-2 levels were four- to fivefold lower in PL-fed mice (P < 0.05). p53 expression/activity was increased in PL-fed versus vehicle-fed then UV-irradiated mice. UV-induced inflammation was decreased in PL-fed mice, as shown by approximately 60% decrease (P < 0.001) in neutrophil infiltration at 24 hours, and macrophages by approximately 50% (<0.02) at 24 and 48 hours. By 72 hours, 54 +/- 5% cyclobutane pyrimidine dimers remained in vehicle-fed versus 31 +/- 5% in PL-fed skin (P < 0.003). The number of 8-hydroxy-2'-deoxyguanosine-positive cells were decreased before UV irradiation by approximately 36% (P < 0.01), suggesting that PL reduces constitutive oxidative DNA damage. By 6 and 24 hours, the number of 8-hydroxy-2'-deoxyguanosine-positive cells were approximately 59% (P < 0.01) and approximately 79% (P < 0.03) lower in PL-fed versus vehicle-fed mice. Finally, UV-induced mutations in PL-fed-mice were decreased by approximately 25% when assessed 2 weeks after the single UV exposure. These data demonstrate that PL extract supplementation affords the following photoprotective effects: p53 activation and reduction of acute inflammation via Cox-2 enzyme inhibition, increased cyclobutane pyrimidine dimer removal, and reduction of oxidative DNA damage.