2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent and persistent environmental toxin that induces hepatotoxicity and increases endotoxin-induced liver injury. The objective of this study was to evaluate whether TCDD could modulate apoptosis and cytokine-controlled apoptotic signaling pathways following lipopolysaccharide (LPS) exposure in female B6C3F1 mice. The effects of TCDD treatment were most dramatic late in the time course (10-14 days posttreatment). Serum enzyme activities were elevated at day 10 (100 microg TCDD/40 microg LPS treatment) and day 14 (100 microg TCDD/saline treatment), indicating peak liver damage occurred at those times. Histological examination of perfused livers showed an increase in apoptotic cells at day 14 in animals treated with 10 microg TCDD. Caspase-1 activity was suppressed at 14 days in mice treated with 100 microg TCDD/40 microg LPS and 100 microg TCDD/4 microg LPS compared to the respective corn oil (CO)/LPS-treated controls. Caspase-3 activity was suppressed at 14 days in 100 microg TCDD/saline-100 microg TCDD/40 microg LPS- and 100 microg TCDD/4 microg LPS-treated mice compared to respective CO/saline- or CO/LPS-treated control mice. At 40 microg LPS, caspase activity was stimulated in TCDD (100 microg)-exposed mice at 3 and 7 days and then suppressed at 10 and 14 days. Western blot analysis, electrophoretic mobility shift assay, and ELISA did not show any effect by TCDD (100 microg) on IkappaB-beta and IkappaB-alpha protein expression or on DNA binding activity of the nuclear NFkappaB protein. These data indicate that TCDD induces apoptosis 14 days posttreatment; however, we found no evidence of suppression of the antiapoptotic transcription factor NFkappaB.

We investigated the role of the inducible isoform of cyclooxygenase (COX-2) in a rat model of periodontitis using a selective COX-2 inhibitor NS-398. Periodontitis was produced by a silk ligature placed around the lower left 1st molar. Animals were treated with NS-398 (3 mg kg(-1) i.p., 2 times per day for 7 days) or vehicle. At Day 8, the gingivomucosal tissues encircling the mandibular 1st molars were removed on both sides for COX-2 immunohistochemistry, measurement of plasma extravasation by the Evans blue technique, and alveolar bone loss by videomicroscopy. Immunohistochemical analysis revealed numerous strongly COX-2-positive cells in the subepithelial tissues in the ligated side and only a few COX-2-reactive cells in the contralateral (control) side. Ligation significantly increased Evans blue extravasation in the gingivomucosal tissue and alveolar bone destruction compared to the control side. NS-398 treatment significantly reduced the plasma extravasation and alveolar bone resorption of the ligated side compared to vehicle administration. The present results suggest that COX-2 is induced by periodontitis, and plays an important role in gingival inflammation and alveolar bone destruction. In a previous study (Br J Pharmacol 1998;123:353-60) we found the expression of the inducible isoform of nitric oxide synthase in this model. Therefore, based on our own data and the literature, we propose that selective inhibition of these inducible enzymes might be a basis for adjunctive therapy, or new therapeutic approaches in periodontitis.

An increase in nitric oxide production has been demonstrated in periodontitis. Here we investigated the potential role of nitric-oxide-derived nitrating species (such as peroxynitrite) in a rat model of ligature-induced periodontitis. Formation of 3-nitrotyrosine, the stable product formed from tyrosine reacting with nitric-oxide-derived nitrating species, was detected in the gingivomucosal tissue. 3-Nitrotyrosine immunohistochemical analysis revealed a significant elevation in the number of immunopositive leukocytes, and higher immunoreactivity of the gingival ligaments and epithelium in the ligated than in the contralateral (control) side. On both sides, several 3-nitrotyrosine-positive bands and, on the ligated side, a unique 52-kDa 3-nitrotyrosine-positive band were detected by Western blot. However, in the sterile gingivomucosal tissue of rat pups, no 3-nitrotyrosine or inducible nitric oxide synthase immunoreactivity was found. Analysis of these data suggests that resident bacteria of the gingivomucosal tissue induce an increase in reactive nitrogen species, which is greatly enhanced by plaque formation in periodontitis.

Poly (ADP-ribose) polymerase (PARP) is a ubiquitous nuclear enzyme that, when activated by free-radical induced DNA damage, contributes to energy failure and cell death in models of central nervous system ischemia and reperfusion. PARP contributes to neuronal cell death in vivo after cerebral ischemia/reperfusion, however, the role of PARP in the pathogenesis of traumatic brain injury (TBI) is unknown. We hypothesized that, compared to wild type mice (+/ +), mice deficient in PARP (-/-) would have reduced motor and cognitive deficits after TBI. Mice underwent controlled cortical impact (CCI) (6 m/s, 1.2 mm depth) and were tested for motor (d 1–5) and cognitive (d 14–18) function after CCI. PARP -/- mice demonstrated improved motor performance and improved cognitive function after CCI (both p < 0.05 compared to +/+). This is the first study to evaluate a role for PARP in functional outcome after TBI. The results suggest a detrimental role for PARP in the pathogenesis of TBI.

Poly(ADP-ribose) polymerase (PARP), or poly-(ADP-ribose) synthetase, is a nuclear enzyme that consumes NAD when activated by DNA damage. The role of PARP in the pathogenesis of traumatic brain injury (TBI) is unknown. Using a controlled cortical impact (CCI) model of TBI and mice deficient in PARP, the authors studied the effect of PARP on functional and histologic outcome after CCI using two protocols. In protocol 1, naïve mice (n = 7 +/+, n = 6 –/–) were evaluated for motor and memory acquisition before CCI. Mice were then subjected to severe CCI and killed at 24 hours for immunohistochemical detection of nitrated tyrosine, an indicator of peroxynitrite formation. Motor and memory performance did not differ between naïve PARP +/+ and –/– mice. Both groups showed nitrotyrosine staining in the contusion, suggesting that peroxynitrite is produced in contused brain. In protocol 2, mice (PARP +/+, n = 8; PARP –/–, n = 10) subjected to CCI were tested for motor and memory function, and contusion volume was determined by image analysis. PARP –/– mice demonstrated improved motor and memory function after CCI versus PARP +/+ mice (P < 0.05). However, contusion volume was not different between groups. The results suggest a detrimental effect of PARP on functional outcome after TBI.

Thurman, R.; Ikejima, K.; Iimuro, Y.; Forman, D.; Zhong, Z.; Qu, W.; Stachlewitz, R. Author Information