Identification of a Kavain Analog with Efficient Anti-inflammatory Effects

Abstract

Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 μg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.

A therapeutic oxygen carrier isolated from Arenicola marina decreased P. gingivalis induced inflammation and tissue destruction

“…However, M101 decreased this exacerbated RANTES response in P. gingivalis-infected EC. Similar trend of results was seen in P. gingivalis-infected macrophages treated with an anti-inflammatory kavain analogue 57 . Moreover, IP-10 release from P. gingivalis-infected EC was down-regulated with M101 treatment.…”

“…TRAP assay also demonstrated greater osteoclastic activity in control mice compared to those treated with M101. Similar pattern of reduced inflammation and tissue damage has also been demonstrated using the same model of P. gingivalis -induced subcutaneous calvarial lesion treated with other potential pharmacological therapeutic agents such as miRNA (mmu-miR-155-5p) 89 , anti-inflammatory kavain analogue 57 and probiotic 90 .…”

Akkermansia muciniphila reduces Porphyromonas gingivalis‐induced inflammation and periodontal bone destruction

“…Mice were anesthetized by the intraperitoneal injection of ketamine‐xylazine (Akorn Animal Health). The heads of mice were shaved, and P. gingivalis (5 × 10 8 CFU) and A. muciniphila (10 9 CFU) in 100μl of PBS or PBS alone were injected subcutaneously in the four treatment groups with a 30.5‐gauge needle at a point on the midline of the skull between the ears and eyes (Huck et al, , ). Lesions were evaluated each day for 5 days.…”

Kava as a Clinical Nutrient: Promises and Challenges

“…Several studies have optimized the anti-inflammatory potential of kava via medicinal structural modifications of kava compounds. One study evaluated the inhibitory effects of kavain analogs on P. gingivalis-induced inflammation in vitro and in vivo and found that Kava-205Me dose-dependently inhibited TNF-α secretion [ 63 ]. In the same study, Kava-205Me reduced the secretion of other cytokines such as IL-12, eotaxin, RANTES, IL-10 and IFN-γ in murine macrophages.…”