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Anti-inflammatory and antiarthritic effects of piperine

Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models

Research article

Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models

Jun Soo Bang1*, Da Hee Oh1*, Hyun Mi Choi1, Bong-Jun Sur2, Sung-Jig Lim3, Jung Yeon Kim4, Hyung-In Yang5, Myung Chul Yoo6, Dae-Hyun Hahm2 and Kyoung Soo Kim1

For the first time, we have demonstrated that piperine has antirheumatic effects in animal models and anti-inflammatory effects on IL1β-stimulated FLSs. Our results suggest that piperine has potential as a therapeutic drug or dietary supplement.

Thus, further investigations should focus on the development of piperine analogues that have potent efficacy and few adverse effects.

Anti-inflammatory drugs used for treating chronic inflammatory diseases such as rheumatoid arthritis are typically prescribed long term to properly control the disordered immune system.

Thus, there is a strong need to develop safe and effective drugs for the long-term use. Many groups have studied nonsteroidal anti-inflammatory small molecules that were derived from natural sources with the aim of developing new treatments for clinical use [17]. For example, curcumin is a polyphenolic compound derived from the dietary spice, turmeric.

Recently, curcumin has been shown to possess diverse pharmacological properties, including anti-inflammation, antiproliferation, and antiangiogenesis. Currently, curcumin is in phase I of clinical trials [18].

Piperine is also a promising natural source with potential for clinical use. Piper longum Linn. has been used in Asia as a natural treatment for poor peripheral blood circulation [19]. Piper longum Linn. and Piper nigrum Linn. are conventionally used as immune enhancers in Indian traditional medicine [20].

Therefore, piperine has been proven effective indirectly, but its mechanism of action remains unknown. In the present study, we evaluated the anti-inflammatory and antiarthritic effects of piperine to determine whether it had therapeutic potential for the treatment of arthritis.

We found that piperine significantly inhibited the production of two important proinflammatory mediators, IL6 and PGE2, in IL1β-stimulated human FLS. This result was consistent with other studies that showed potent anti-inflammatory effects in other systems. The inhibition of PGE2 production is important due to its central role in triggering pain. In addition, MMP1 and MMP13 collagenases play dominant roles in RA and osteoarthritis because they are the rate-limiting components of the collagen degradation process. The significant inhibition of MMP13 expression is particularly important because it degrades a wide range of collagenous and non-collagenous extracellular matrix macromolecules and is remarkably active against collagen type II, the predominant collagen in cartilage.

To our knowledge, this is the first report to show that piperine inhibited the expression of MMP13 in IL1β-stimulated FLSs. We also investigated the molecular mechanisms underlying piperine inhibition. We found that piperine did not significantly inhibit the activation of MAP kinase or IκB kinase signaling pathways. At the maximum concentration tested (100 μg/ml), piperine slightly inhibited the phosphorylation of ERK1/2 stimulated by IL1β. Piperine also inhibited the activation of the transcription factor AP-1, but not NFκB, in our system. However, a previous study in B16F-10 melanoma cells showed that piperine was able to inhibit the activation of several transcription factors, including NFκB, c-FOS, cAMP response element binding (CREB) and activating transcription factor 2 (ATF-2).

Accordingly, in that study, it significantly reduced the production of IL1β, tumor necrosis factor (TNF)α, IL6, and granulocyte-macrophage colony stimulating factor (GM-CSF) [21].

We used two animal models to evaluate the in vivo analgesic or antiarthritic effects of piperine. We found that piperine (100mg/kg) effectively improved the symptoms of arthritic diseases with an effect comparable to prednisolone, although at 20 mg/kg, piperine did not have a significant analgesic effect in the arthritic animal model.

One of the major drawbacks of the current study was the large amount of piperine administered. Though the effects of 100 mg/kg piperine were therapeutic, several other studies have shown in vivo effects with doses below 50 mg/kg [22-24].

Furthermore, in this study, the effects reached significance at 8 or 9 days. Thus, the potency of piperine was relatively weak compared to 10 mg/kg prednisolone, which showed significant effects at 4 or 5 days. The in vivo toxicity of a 100 mg/kg dose piperine has not been tested; however, rats did not exhibit any adverse effects and they survived throughout the experiments. Nevertheless, piperine was shown to have immunotoxicological effects in mice at a dose of 2.25 mg/kg [25].

Piperine is also known to enhance the bioavailability of some drugs by inhibiting drug metabolism or by increasing absorption [18,24,26]. Thus, piperine may prove to be useful on combination treatments with other drugs. For example, a combination of gallic acid and piperine reduced berylliuminduced hepatorenal dysfunction and the associated oxidative stress [22]. In addition, a synergistic effect of piperine was demonstrated in a clinical study that tested the pharmacokinetics of nevirapine, a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase [27]. The combination therapy was well tolerated, with few or no clinical adverse effects, and the mean maximum plasma concentration of nevirapine was increased when combined with piperine. In another clinical study, piperine was shown to increase the plasma levels of coenzyme Q10 [28].

Therefore, piperine may improve the therapeutic effect or lower the dose requirements of other drugs when administrated with DMARDs as a therapeutic drug or dietary supplement. In addition, combinations of DMARDs with piperine may reduce the side effects of DMARDs.

Research article HERE