Novel anti-nociceptive effects of cardamonin via blocking expression of cyclooxygenase-2 and transglutaminase-2
Graphical abstract
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.
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2021, Current Research in Pharmacology and Drug DiscoveryCitation 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 PharmacologyCitation 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 PharmacologyCitation 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 ImmunopharmacologyCitation 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.
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These authors contributed equally.