Abstract
Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by cellular infiltration and proliferation of synovium, leading to progressive destruction of the joints [1]
Concerning the arthritic index, concurrent treatment of arthritic rats with methotrexate and Bee venom (BV) showed a significant improvement in arthritis severity at the end of the experiment as compared to arthritic non treated rats and rats treated with methotrexate alone, while methotrexate treatment didn’t show any improvement from the arthritic non treated rats throughout the experiment (Fig. 2A)
Combined treatment showed earlier significant increase in paw withdrawal latency (PWL) starting from day 6 and continued to increase till reaching 500 and 242% on day 21, as compared to the change in arthritic non treated rats as well as rats treated with methtrexate alone, respectively
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by cellular infiltration and proliferation of synovium, leading to progressive destruction of the joints [1]. Proinflammatory cytokines like interleukin-1 and tumor necrosis factor-alpha (TNF-a) are highly expressed in the rheumatoid joint and play a key role in the pathogenesis of RA [2]. These cytokines stimulate the release of chemokines, metalloproteinases, prostaglandin E2 and cycloxygenase-2 from synoviocytes which promote further inflammation, hyperplasia and cartilage destruction [3]. Serum and joint tissue TNF-a is usually elevated in those patients [6], the use of TNF-a inhibitors suppresses the disease activity
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