Bioavailability, anti-inflammatory and anti-arthritic effect of Acetyl Keto Boswellic acid and its combination with methotrexate in an arthritic animal model

Abstract

Ethnopharmacological relevance: Rheumatoid arthritis is one of the most common disabling chronic progressive autoimmune diseases affecting the adult world population. Boswellia serrata has been a known anti-inflammatory agent since ancient times. Therefore, research on Boswellia extract based on Acetyl Keto Boswellic Acid (AKBA) content evaluating its efficacy and safety is necessary. The study aimed to find a suitable Boswellia extract rich in AKBA to evaluate its bioavailability, anti-inflammatory, and anti-arthritic effect. In addition, the synergistic action of AKBA extract with methotrexate (MTX) was also assessed on an animal model.

Materials and methods: Oral bioavailability of AKBA and the anti-inflammatory activity of 10% AKBA (5, 10, 20, 40 mg/kg b.w) was assessed and compared with 2% AKBA (40 mg/kg) and diclofenac (10 mg/kg). The effect of 10% AKBA at 20 mg/kg and 40 mg/kg was evaluated in the FCA induced arthritis animal model alone and combined with methotrexate (MTX) at 2 mg/kg b.w. Subplantar injection of FCA produced edema within a few hours with progressive arthritis by the 9th day after injection. All the treatments were initiated from the 10th day until the 45th day. Oral administration of 10% AKBA was done daily and MTX by intraperitoneal route once a week from day 10 to day 45. Paw volume, erythrocyte sedimentation rate (ESR), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, oxidative markers (superoxide dismutase (SOD) levels, malondialdehyde (MDA), total proteins and liver histopathology were examined.

Results: 10% AKBA provided 8.48-fold, 24.22-fold, 47.36-fold, and 110.53-fold higher AUC (0-α) of AKBA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively compared to 2% AKBA at 40 mg/kg. Percentage paw edema inhibition of 10% AKBA at 20 mg/kg and 40 mg/kg were significantly higher than 2% regular AKBA (40 mg/kg) and diclofenac (10 mg/kg). 10% AKBA at a dose of 20 and 40 mg/kg significantly reduced ESR compared with FCA treated group. A combination of methotrexate with 10% AKBA showed the highest reduction in ESR. 10% AKBA at both dose levels significantly reduced hepatic marker enzymes and total bilirubin levels. Treatment with 10% AKBA showed a significant increase in total proteins, antioxidant enzymes and a decrease in malondialdehyde levels. Similarly, 10% AKBA protected the hepatocytes compared with the FCA and FCA + MTX treated group. 10% AKBA was capable of significantly minimizing FCA and FCA + MTX induced changes.

Conclusion: Anti-inflammatory activity of AKBA due to inhibition of lipoxygenase (LOX) enzymes supports the use of AKBA in inflammatory disorders. Combination therapy of 10% AKBA with MTX is effective in inhibiting arthritis and circumventing hepatotoxicity produced by MTX in arthritic animals.

Keywords: Acetyl keto boswellic acid; Anti-inflammatory; Anti-oxidant; Arthritis; Hepatoxicity; Methotrexate.