A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats

Sugita, Ryusuke; Kuwabara, Harumi; Sugimoto, Kotaro; Kubota, Kazufumi; Imamura, Yoshiaki; Kiho, Toshihiro; Tengeiji, Atsushi; Kawakami, Katsuhiro; Shimada, Kohei

doi:10.1007/s10753-016-0323-5

Cited by 18 publications

(14 citation statements)

References 29 publications

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“…It was reported that the genetic inhibition of iNOS reduced the degree of macrophage inflammation caused by LPS [16]. It has also been shown that selective PGE 2 synthesis inhibitors can relieve pyrexia and chronic inflammation in rats [17]. We observed that the up-regulated expression of iNOS and COX-2 and the excessive production of NO and PGE 2 were abolished in the presence of CBTE.…”

Section: Discussionsupporting

confidence: 54%

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Kim

Park

Hwangbo

et al. 2017

BMC Complement Altern Med

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BackgroundCheongsangbangpung-tang (CBT) is a traditional herbal formula used in Eastern Asia to treat heat-related diseases and swellings in the skin. The present study was conducted to evaluate the anti-inflammatory effects of cheongsangbangpung-tang extract (CBTE) both in vitro and in vivo.MethodsThe in vitro effects of CBTE on the lipopolysaccharide (LPS)-induced production of inflammation-related proteins were examined in RAW 264.7 cells. The levels of nitric oxide (NO) were measured with the Griess reagent. Inflammatory cytokines and prostaglandin E2 (PGE2) were detected using the enzyme-linked immunosorbent assay (ELISA) method. Inflammation-related proteins were detected by Western blot. The effect of CBTE on acute inflammation in vivo was evaluated using carrageenan (CA)-induced paw oedema. To evaluate the anti-inflammatory effect, paw oedema volume, thickness of the dorsum and ventrum pedis skin, number of infiltrated inflammatory cells, and number of COX-2-, iNOS-immunoreactive cells were measured.ResultsIn an in vitro study, CBTE inhibited the production of NO and PGE2 and also decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) activity, interleukin (IL)-1β, IL-6 and tumuor necrosis factor-α. In LPS-activated macrophages, nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signalling is a pivotal pathway in the inflammatory process. These plausible molecular mechanisms increased the phosphorylation of I-κBα, while the activation of NF-κB and the phosphorylation of MAPK by LPS were blocked by CBTE treatment. In our in vivo study, a CA-induced acute oedematous paw inflammation rat model was used to evaluate the anti-inflammatory effect of CBTE. CBTE significantly reduced the increases in paw swelling, skin thicknesses, infiltrated inflammatory cells and iNOS-, COX-2 positive cells induced by CA injection.ConclusionsBased on these results, CBTE should favourably inhibit the acute inflammatory response through modulation of NF-κB activation and MAPK phosphorylation. Furthermore, the inhibition of CBTE in rat paw oedema induced by CA is considered to be clear evidence that CBTE may be a useful source to treat inflammation.

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Section: Discussionsupporting

confidence: 54%

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Kim

Park

Hwangbo

et al. 2017

BMC Complement Altern Med

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“…Prostaglandin E 2 is thought to be the most dominant proinflammatory prostaglandin and plays a major role in inflammatory symptoms (Sugita et al, 2016). It was clear that the level of prostaglandin E 2 were significantly elevated in acetic acid control group when compared to normal control group (p50.05).…”

Section: Resultsmentioning

confidence: 93%

Comparative pharmaceutical study on colon targeted micro-particles of celecoxib:in-vitro–in-vivoevaluation

et al. 2016

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In order to target celecoxib which is a COX2 inhibitor, with potentials in the prevention and treatment of colitis and colon cancer, it was formulated as microparticles using the solvent/ evaporation method and various pH-dependent Eudragit polymers. The in-vitro evaluation of the prepared microparticles showed spherical and smooth morphology. The encapsulation efficiency and yield were high, indicating that the method used is simple and efficient at this scale. The in-vitro release study showed no release in the acidic medium for 2 h followed by the release of the drug in pH 6.8 in case of Eudragit L100-55 and L100 and pH 7.4 in case of Eudragit S100. The pharmacokinetic parameters were calculated and method validation was performed to insure that it is suitable and reliable. Pharmacokinetic parameters were investigated by determining the C max , T max , AUC 0-t , K el , and t 1/2 of the drug as a suspension and as microparticles. There was a significant difference (p50.05) in T max between the drug as a suspension and as microparticles. The effect of celecoxib on the degree of inflammation was examined on acetic acid induced colitis rat model and the drug was given as a suspension and as microparticles. The evaluation was done using macroscopical, microscopical and biochemical examination. There was a significant difference between the acetic acid control group and the treatment groups regarding all examination criteria in the order microparticles formulated using Eudragit S100 followed by Eudragit L100-55 while microparticles using Eudragit L100 and drug suspension showed almost the same results.

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“…Each experiment was performed in duplicate. The results of LPS(−), LPS(+), and celecoxib (positive control) were the same as our published paper [ 17 ] because this experiment was performed in the same plate.…”

Section: Methodsmentioning

confidence: 52%

“…Traditional NSAIDs or COX-2 inhibitors are widely used to treat these symptoms. We previously reported that a novel selective PGE 2 synthesis inhibitor shows antipyretic and anti-inflammatory effects [ 17 ]. In the present study, we evaluated the analgesic potential of our compound in inflammatory pain models.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have discovered quinoline derivatives which are orally available and have a potent inhibitory effect on PGE 2 synthesis in rats. We have revealed that these compounds are highly selective for PGE 2 synthesis inhibition [ 17 , 18 ], and we have previously reported the antipyretic and anti-inflammatory profile of compound A in a rat LPS-induced pyrexia and adjuvant-induced arthritis model [ 17 ]. In the present study, we evaluated analgesic effects of another quinoline derivative, compound I, in acute and chronic inflammatory pain models.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous Inhibition of PGE₂and PGI₂Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models

Sugita

Kuwabara

Kubota

et al. 2016

Mediators of Inflammation

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Prostaglandin E2 (PGE2) is well known as a mediator of inflammatory symptoms such as fever, arthritis, and inflammatory pain. In the present study, we evaluated the analgesic effect of our selective PGE2 synthesis inhibitor, compound I, 2-methyl-2-[cis-4-([1-(6-methyl-3-phenylquinolin-2-yl)piperidin-4-yl]carbonyl amino)cyclohexyl] propanoic acid, in rat yeast-induced acute and adjuvant-induced chronic inflammatory pain models. Although this compound suppressed the synthesis of PGE2 selectively, no analgesic effect was shown in both inflammatory pain models. Prostacyclin (PGI2) also plays crucial roles in inflammatory pain, so we evaluated the involvement of PGI2 signaling in rat inflammatory pain models using prostacyclin receptor (IP) antagonist, RO3244019. RO3244019 showed no analgesic effect in inflammatory pain models, but concomitant administration of compound I and RO3244019 showed analgesic effects comparable to celecoxib, a specific cyclooxygenase- (COX-) 2 inhibitor. Furthermore, coadministration of PGE2 receptor 4 (EP4) antagonist, CJ-023423, and RO3244019 also showed an analgesic effect. These findings suggest that both PGE2 signaling, especially through the EP4 receptor, and PGI2 signaling play critical roles in inflammatory pain and concurrent inhibition of both signals is important for suppression of inflammatory hyperalgesia.

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A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats

Cited by 18 publications

References 29 publications

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Comparative pharmaceutical study on colon targeted micro-particles of celecoxib:in-vitro–in-vivoevaluation

Simultaneous Inhibition of PGE₂and PGI₂Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models

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A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats

Cited by 18 publications

References 29 publications

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Cheongsangbangpung-tang ameliorated the acute inflammatory response via the inhibition of NF-κB activation and MAPK phosphorylation

Comparative pharmaceutical study on colon targeted micro-particles of celecoxib:in-vitro–in-vivoevaluation

Simultaneous Inhibition of PGE2and PGI2Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models

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Product

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Simultaneous Inhibition of PGE₂and PGI₂Signals Is Necessary to Suppress Hyperalgesia in Rat Inflammatory Pain Models