Reduction of Articular and Systemic Inflammation by Kava-241 in a Porphyromonas gingivalis-Induced Arthritis Murine Model

Abstract

Rheumatoid arthritis (RA) is an inflammatory disease that has been linked to several risk factors, including periodontitis. Identification of new anti-inflammatory compounds to treat arthritis is needed. We had previously demonstrated the beneficial effect of Kava-241, a kavain-derived compound, in the management of -induced periodontitis. The present study evaluated systemic and articular effects of Kava-241 in an infective arthritis murine model triggered by bacterial inoculation and primed with a collagen antibody cocktail (CIA) to induce joint inflammation and tissular destruction. Clinical inflammation score and radiological analyses of the paws were performed continuously, while histological assessment was obtained at sacrifice. Mice exposed to and a CIA cocktail and treated concomitantly with Kava-241 exhibited a reduced clinical inflammatory score and a decreased number of inflammatory cells and osteoclasts within joint. Kava-241 treatment also decreased significantly tumor necrosis factor alpha (TNF-α) in serum from mice injected with a Toll-like receptor 2 or 4 (TLR-2/4) ligand,-lipopolysaccharide (LPS). Finally, bone marrow-derived macrophages infected with and exposed to Kava-241 displayed reduced TLR-2/4, reduced mitogen-activated protein kinase (MAPK)-related signal elements, and reduced LPS-induced TNF-α factor (LITAF), all explaining the observed reduction of TNF-α secretion. Taken together, these results emphasized the novel properties of Kava-241 in the management of inflammatory conditions, especially TNF-α-related diseases such as infective RA.

Porphyromonas gingivalis triggers the shedding of inflammatory endothelial microvesicles that act as autocrine effectors of endothelial dysfunction

“…gingivalis was previously demonstrated as a specific TLR4-dependent endothelial actor in pro-inflammatory TNF-α and IL-6 secretion following endothelial invasion or via its virulence factors such as LPS 55,56 . Moreover, several studies demonstrated the importance of NF-K B pathways in P. gingivalis elicited inflammation in several cell types [57][58][59][60] . In a previous report, we were able to demonstrate that TLR4 + MV generated by Pseudomonas were true mediators of NF-K B-dependent signaling in TLR4 − HEK engineered cells via I K B phosphorylation 61 .…”

Kava as a Clinical Nutrient: Promises and Challenges

“…Furthermore, Kava-205Me improved the rate of wound healing associated with soft tissue inflammation and osteoclast activation in a model of acute P. gingivalis-induced calvarial destruction, as well as inducing a reduction in paw swelling and joint destruction. Another kavain analog, namely Kava-241, decreased the number of inflammatory cells and osteoclasts within the joints of mice exposed to P. gingivalis, as well as decreasing serum TNF-α [ 62 ]. The potential of kavalactone analogs in reducing P. gingivalis-induced TNF-α production was also shown in macrophages [ 66 ].…”

Proposal for a novel murine model of human periodontitis using Porphyromonas gingivalis and type II collagen antibody injections

“…Pathogen-free DBA1/BO male mice (Taconic Farm, Rensselaer, NY) were used in this study (Huck et al, 2018). Pathogen-free female mice with ovariectomy were not used to be consistent with prior protocols (Huck et al, 2018). Mice were fed sterile food and distilled water ad libitum .…”