TNF-a is an important cytokine mediator of inflammation which suggests that inhibition of TNF-a activity may provide potential for clinical application. Recent data indicated that treatment of both human and mouse cells with Kavain significantly modulates P. gingivalis- and LPS-induced TNF-α expression. In order to obtain a selective analog with optimized biological activity and structural physico-chemical properties of Kavain, Kavain analogs were designed and synthesized and found one Kavain analogue (named Kav001) that is similar to Kavain but soluble and does not induce a significant toxicity. Both studies in vitro and in vivo treatment by Kav001 showed stronger biological function as compared to Kavain. Furthermore, most mouse bone marrow macrophages up-regulated Bcl-6 while down-regulating LITAF expression after treatment with Kav001 for 36 h. Consequently, this led to an extension of macrophage pseudopods due to its immune response to P.g. infection/ LPS stimulation. we further found that Kav001 not only inhibits TNF-α, but also IL-1β, IL-6, caspase 1 and neutrophil infiltration in response to LPS. However, this phenomenon cannot be observed when macrophages were treated with LPS plus Kavain. We believe that Kav001 may mediate a novel link between Kav001 and LPS-induced inflammation and may be used as a key inhibitor to LPS-induced inflammation/inflammatory disease.

BACKGROUND: The aim of this study was to assess the effects of a modified Kavain-derived compound, Kava-241, on periodontal destruction in a periodontitis-induced murine model. METHODS: The study involved 49 mice divided into three groups: control, diseased, and treatment. Diseased mice were infected with P. gingivalis via oral gavage over a 15-day period to mimic periodontal infection. Treated mice received Kava-241 treatment after disease induction over the same period. Bone loss and inflammatory cell activity was assessed by a morphometric analysis of the left mouse maxillae and a histomorphometric analysis of TRAP and H&E stained tissue sections of the right mouse maxillae. RESULTS: Infected group showed significantly increased alveolar bone loss and inflammatory cells throughout the experimental period in comparison to the untreated control groups. The Infected mice that received Kava-241 showed a significant decrease in inflammatory cell activity in periodontal connective tissues as compared to mice that did not receive any treatment. In periodontal connective tissues, treated mice showed significant decreases of 61.9% and 41.6% of polymorphonucleocyte and monocyte cell counts, respectively, compared to untreated mice. Furthermore, the mice that received treatment post-infection showed a statistically significant decrease in alveolar bone loss. Histomorphometric analysis demonstrated 72.7% and 37.0% reductions of epithelial down-growth and bone loss respectively. Morphometric analysis demonstrated a 46.7% reduction of bone loss in treated mice compared to controls. CONCLUSION: Our results demonstrate modification of Kava could yield a more effective and safer therapeutic compound in the treatment of periodontal inflammation and bone loss.