Novel anti-nociceptive effects of cardamonin via blocking expression of cyclooxygenase-2 and transglutaminase-2

https://doi.org/10.1016/j.pbb.2013.12.019Get rights and content

Highlights

  • Cardamonin suppressed expression of cyclooxygenase-2 and transglutaminase-2.

  • Transglutaminase-2 is involved in IL-1b-induced expression of cyclooxygenase-2.

  • Cardamonin suppressed PBQ-induced writhing and carrageenan-induced hyperalgesia.

Abstract

Recently, we reported that Alpinia katsumadai (AK) has anti-nociceptive activity in vivo and that cardamonin (CDN) from AK suppresses the activity and expression of transglutaminase-2 (Tgase-2). However, it remains unknown whether CDN contributes to the anti-nociceptive activities of AK in vivo. We examined the anti-inflammatory effects of CDN in MG63 osteoblast-like cells and Raw264.7 macrophage-like cells treated with interleukin-1β treatment. CDN suppressed the expression of Tgase-2, cyclooxygenase-2 (COX-2), and p65 (nuclear factor-κB) in a concentration-dependent manner, and restored the expression of IκB in MG63 and Raw264.7 cells. However, CDN did not inhibit the activity of COX-2. Gene silencing of Tgase-2 reduced the COX-2 expression in MG63 cells. Phenylbenzoquinone (PBQ)-induced writhing, carrageenan-induced hyperalgesia, and rota-rod test were used to evaluate the anti-nociceptive activity in vivo. CDN (3–30 mg/kg, orally administered) significantly inhibited PBQ-induced writhing. CDN also produced a significant, dose-dependent increase in the withdrawal response latencies in carrageenan-induced hyperalgesia. The effects of CDN on PBQ-induced writhing were not caused by impaired motor functions. These results suggest that CDN might be helpful in controlling the pain from inflammatory diseases.

Introduction

Nociception is the process by which intense mechanical, thermal, or chemical stimuli are detected by nociceptors through the activation of many types of ionotropic channels and metabotropic receptors (Rodrigues et al., 2012, Tominaga, 2007). In addition, when tissue damage and inflammation occur, the inflammatory mediators released at the inflammatory site can directly activate or sensitize the nociceptors for other stimuli (Schaible and Richter, 2004). Pain that is unyielding to the typical analgesic drugs is a major unmet need for patients (Renfrey et al., 2003). Although selective cyclooxygenase-2 (COX-2) inhibitors are effective in certain types of chronic pain, their well-known side effects including increased risks of heart attack and stroke restrict their use (Grosser et al., 2006). Therefore, opioid narcotics are the most effective treatments for acute and chronic pain. However, their clinical utility is nearly always restricted due to the development of analgesic tolerance and painful hypersensitivity, such as morphine-induced hyperalgesia (Ossipov et al., 2004, Salvemini et al., 2011). Therefore, alternatives are needed to control the symptoms of pain. It is reasonable to investigate plant extracts to find novel means of improving the symptoms of atopic dermatitis considering the multifactorial aspects of disease (Choi et al., 2009).

Alpinia katsumadai (AK) has been widely used in traditional Chinese and Korean medicine to treat a variety of conditions including emesis and gastric disorders, such as gastric pain and distended abdomen. It also has significant anti-oxidant and anti-emetic activities, and inhibits prostaglandin production in lipopolysaccharide-stimulated mouse peritoneal macrophages (Lee et al., 2003, Noh et al., 1998, Yang et al., 1999). In addition, we recently reported that AK has anti-nociceptive activity (Choi et al., 2010). However, it is not clear as to which compounds from AK are key components possessing anti-nociceptive activity.

Cardamonin (CDN, 2′,4′-dihydroxy-6′-methoxychalcone) is a well-known component of AK (Wang et al., 2007). CDN has anti-tumor, and anti-inflammatory activities (Chow et al., 2012, Yadav et al., 2012). CDN inhibits the production of proinflammatory mediators in whole blood or human monocytes (Ahmad et al., 2006, Hatziieremia et al., 2006). Recently, CDN was reported to block the migration of cancer cells via inhibiting expression and activity of transglutaminase-2 (Tgase-2) (Park et al., 2013).

Presently, we demonstrate that CDN suppressed the expression of COX-2 and Tgase-2 in MG63 osteoblast-like cells and Raw264.7 cells, and reduces PBQ-induced writhing and carrageenan-induced hyperalgesia.

Section snippets

Chemicals and animals

Indomethacin, carrageenan and phenylbenzoquinone (PBQ) were purchased from Sigma-Aldrich (St. Louis, MO, USA). All male ICR mice (5–6-weeks-of-age) and male, Sprague-Dawley rats (6–7-weeks-of-age) used in the present study were purchased from Samtako Korea and were maintained under specific pathogen-free conditions until required. The animals were housed under standard conditions (22 ± 2 °C, 50 ± 10% humidity and a 12-h light–dark cycle) with free access to water and a regular diet. All experiments

Effects of CDN on cyclooxygnease-2 and Tgase-2 in MG63 and Raw264.7 cells

To evaluate the anti-nociceptive activity of CDN, we first examined the effects of CDN on expressions of COX-2 and Tgase-2 in osteoblast-like MG63 cells and macrophage-like Raw264.7 cells that had been treated with interleukin (IL)-1β treatments. CDN suppressed the expressions of Tgase-2, COX-2 and p65 (NF-κB), and restored IκB expression in MG63 cells (Fig. 1A) and Raw264.7 cells (Fig. 1B). Since AK inhibits COX-2 activity (Choi et al., 2010), we examined whether CDN inhibited COX-2 activity.

Discussion

Chronic pain affects 116 million people in the United States, more than the total affected by diabetes, heart disease, and cancer (Medicine, 2011). In the United States, lost productivity and treatment costs for pain exceed 635 billion dollars per year (Medicine, 2011). Pain is the primary reason patients with inflammatory arthritis seek rheumatologic care. Among rheumatoid arthritis patients, 68–90% rate pain as one of their top three priorities (Heiberg et al., 2005, ten Klooster et al., 2007).

Conflict of interest

Nothing to declare.

Acknowledgments

This work was supported by the Dongguk University Research Fund of 2010.

References (43)

  • J.B. Calixto et al.

    Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules

    Planta Med

    (2004)
  • S.Z. Choi et al.

    Novel botanical drug for the treatment of diabetic neuropathy

    Arch Pharm Res

    (2011)
  • J.K. Choi et al.

    Antinociceptive effects of Alpinia katsumadai via cyclooxygenase-2 inhibition

    Biomol Ther

    (2010)
  • P. Dey et al.

    Neuropharmacological properties of Mikania scandens (L.) Willd. (Asteraceae)

    J Adv Pharm Technol Res.

    (2011)
  • T. Faunce et al.

    The Vioxx pharmaceutical scandal: Peterson v Merke Sharpe & Dohme (Aust) Pty Ltd

    J Law Med

    (2010)
  • E.A. Formukong et al.

    Analgesic and antiinflammatory activity of constituents of Cannabis sativa L

    Inflammation

    (1988)
  • T. Grosser et al.

    Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities

    J Clin Invest

    (2006)
  • S. Hatziieremia et al.

    The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFkappaB signalling pathways in monocytes/macrophages

    Br J Pharmacol

    (2006)
  • T. Heiberg et al.

    Seven year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis

    Ann Rheum Dis

    (2005)
  • L.C. Hendershot et al.

    Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics

    J Pharmacol Exp Ther

    (1959)
  • S.Y. Kim

    Transglutaminase 2: a new paradigm for NF-kappaB involvement in disease

    Adv Enzymol Relat Areas Mol Biol

    (2011)
  • Cited by (18)

    • Emerging roles of cardamonin, a multitargeted nutraceutical in the prevention and treatment of chronic diseases

      2021, Current Research in Pharmacology and Drug Discovery
      Citation Excerpt :

      Although the exact mechanism of the antinociceptive property of CD is poorly known, it was reported that CD modulate transient receptor potential cation channel subfamily V member 1 (TRPV₁), glutamate, and opioid receptors which would help in relieving the pain (Ping et al., 2018; Nesello et al., 2016). In another study, CD was shown to suppress inflammatory molecules and enzymes such as IL-1β-induced, COX-2, and transglutaminase (Tgase-2) expression in MG63 and Raw264.7 ​cell lines (Park et al., 2014). Transient receptor potential channels (TRP) are ion channels that modulate the pain signal transduction pathways.

    • Cardamonin attenuates hyperalgesia and allodynia in a mouse model of chronic constriction injury-induced neuropathic pain: Possible involvement of the opioid system

      2017, European Journal of Pharmacology
      Citation Excerpt :

      Based on our findings, the significant differences towards pain stimuli observed between the cardamonin treated groups on day 14 and day 21 indicates better therapeutic outcomes on repeated dose. The anti-inflammatory and antinociceptive effects produced by cardamonin have been previously reported (Ahmad et al., 2006; Israf et al., 2007; Park et al., 2014). In accordance with these findings, cardamonin possibly attenuate neuropathic pain by inhibiting the inflammatory mediators and cytokines partly by inhibiting the downstream intracellular signalling pathway.

    • Cardamonin (2′,4′-dihydroxy-6′-methoxychalcone) isolated from Boesenbergia rotunda (L.) Mansf. inhibits CFA-induced rheumatoid arthritis in rats

      2017, European Journal of Pharmacology
      Citation Excerpt :

      and was previously reported to possess potent anti-inflammatory effect provided the evidence that it was able to inhibit the secretion of TNF-α from induced RAW 264.7 cells as well as the production of other pro-inflammatory mediators in whole blood (Ahmad et al., 2006). Besides, an in vivo study demonstrated that cardamonin possesses effective anti-nociceptive activity in acute inflammatory pain model (Park et al., 2014). Based on the extensive molecular work on cardamonin which yielded favorable anti-inflammatory results, it has led to the present study which aims to investigate the anti-arthritic effect of cardamonin on CFA-induced RA rat model.

    • Anti-inflammatory activities of cardamonin from Alpinia katsumadai through heme oxygenase-1 induction and inhibition of NF-κB and MAPK signaling pathway in the carrageenan-induced paw edema

      2015, International Immunopharmacology
      Citation Excerpt :

      Cardamonin has received interest due to its benefits to humans' health. It possesses various pharmacological effects including anti-nociceptive effect [4], anti-inflammatory activity [5], and anti-tumor activity [6], inhibits vascular smooth muscle cell proliferation and migration [7] and protects against cisplatin-induced nephrotoxicity [8]. In addition, cardamonin may exert its effects via a redox mechanism.

    View all citing articles on Scopus
    1

    These authors contributed equally.

    View full text