Differential regulation of oxidative stress and cytokine production by endothelin ET<sub>A</sub> and ET<sub>B</sub> receptors in superoxide anion-induced inflammation and pain in mice

Fattori, Victor; Serafim, Karla Guivernau Gaudens; Zarpelon, Ana C.; Borghi, Sérgio M.; Pinho‐Ribeiro, Felipe A.; Alves‐Filho, José C.; Cunha, Thiago M.; Cunha, Fernando Q.; Casagrande, Rúbia; Verri, Waldiceu A.

doi:10.1080/1061186x.2016.1245308

Cited by 13 publications

(13 citation statements)

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“…The antioxidant activity is a hallmark of the activity of flavonoids ( Verri et al, 2012 ) and in fact, the reduction of oxidative and nitrosative stress are important mechanisms by which flavonoids ( Anjaneyulu and Chopra, 2003 ; Al-Rejaie et al, 2015 ; Ahmed et al, 2016 ; Pinho-Ribeiro et al, 2016 ) and other molecules ( Fattori et al, 2015 , 2017a ; Singh and Vinayak, 2015 ) act. Moreover, injection of a superoxide anion donor, peroxynitrite, or intrathecal delivery of ROS elicits pain behavior in mice ( Wang et al, 2004 ; Fattori et al, 2015 , 2017b ) indicating that oxidative stress plays important role in pain processing ( Grace et al, 2016 ). Neutrophils produce ROS upon recognition of MSU crystals ( Desaulniers et al, 2001 ) and, in turn, ROS contribute to neutrophil recruitment ( Hattori et al, 2010 ; Sakai et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

et al. 2018

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Gouty arthritis is characterized by an intense inflammatory response to monosodium urate crystals (MSU), which induces severe pain and reduction in the life quality of patients. Trans-Chalcone (1,3-diphenyl-2-propen-1-one) is a flavonoid precursor presenting biological activities such as anti-inflammatory and antioxidant proprieties. Thus, the aim of this work was to evaluate the protective effects of trans-Chalcone in experimental gout arthritis in mice. Mice were treated with trans-Chalcone (3, 10, or 30 mg/kg, per oral) or vehicle (Tween 80 20% plus saline) 30 min before intra-articular injection of MSU (100 μg/knee joint, intra-articular). We observed that trans-Chalcone inhibited MSU-induced mechanical hyperalgesia, edema, and leukocyte recruitment (total leukocytes, neutrophils, and mononuclear cells) in a dose-dependent manner. Trans-Chalcone also decreased inflammatory cell recruitment as observed in Hematoxylin and Eosin (HE) staining and the intensity of fluorescence of LysM-eGFP+ cells in the confocal microscopy. Trans-Chalcone reduced MSU-induced oxidative stress as observed by an increase in the antioxidant defense [Glutathione (GSH), Ferric Reducing (FRAP), and 2,2’-Azinobis-3-ethylbenzothiazoline 6-sulfonic acid (ABTS assays)] and reduction in reactive oxygen and nitrogen species production [superoxide anion (NBT assay) and nitrite (NO assay)]. Furthermore, it reduced in vivo MSU-induced interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and IL-6 production, and increased Transforming growth factor-β (TGF-β) production. Importantly, trans-Chalcone reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and thereby the mRNA expression of the inflammasome components Nlrp3 (cryopyrin), Asc (apoptosis-associated speck-like protein containing a CARD), Pro-caspase-1 and Pro-IL-1β. In vitro, trans-Chalcone reduced the MSU-induced release of IL-1β in lipopolysaccharide (LPS)-primed macrophages. Therefore, the pharmacological effects of trans-Chalcone indicate its therapeutic potential as an analgesic and anti-inflammatory flavonoid for the treatment of gout.

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Section: Discussionmentioning

confidence: 99%

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

et al. 2018

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“…Moreover, tempol reduced superoxide anion-induced TNF α , IL-1 β , preproET-1, and COX-2 mRNA expressions in both paw skin and spinal cord. In fact, targeting these mediators in the paw skin and spinal cord with tempol or with other analgesics (present data, [2, 7, 20–22]) reduced superoxide anion-induced pain and inflammation. Finally, superoxide anion-triggered peripheral inflammation results in spinal cord activation of astrocytes and microglia, which was inhibited by tempol.…”

Section: Discussionmentioning

confidence: 63%

“…PGE 2 sensitizes nociceptor sensory neurons via protein kinase A (PKA) phosphorylation of sodium channels [30]. Furthermore, KO 2 -induced pain depends on ET-1 [21, 22] and COX-2 [20]. Thus, it is conceivable to evaluate whether tempol inhibits KO 2 -induced mRNA expression of COX-2 and preproET-1.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, the inhibition of KO 2 -induced TNF α , IL-1 β , and COX-2 expressions by tempol is an important mechanism for inhibition of hyperalgesia. ET-1 is a hyperalgesic peptide [33], which mediates superoxide anion-induced pain, cytokine production, and oxidative stress [21, 22]. The present data show that tempol inhibited peripheral and spinal cord superoxide anion-induced TNF α , IL-1 β , COX-2, and preproET-1 mRNA expressions, evidencing that tempol treatment reduces the production of a cascade of inflammatory molecules triggered by superoxide anion and that this mechanism might contribute to reducing superoxide anion-induced pain and inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice

Bernardy

Zarpelon

Pinho‐Ribeiro

et al. 2017

BioMed Research International

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The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10–100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO2, 30 μg). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNFα, IL-1β, IL-10, COX-2, preproET-1, gp91phox, Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO2-induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO2 were successfully inhibited by tempol. KO2-induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain.

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“…Neutrophil recruitment to the knee joint was evaluated through the quantification of the enzyme MPO activity, as previously described ( Fattori et al, 2017 ). Briefly, mice were terminally anesthetized, and the knee joint was dissected into 200 μL of 50 mM K 2 HPO 4 buffer (pH 6.0) containing 0.5% HTAB and then homogenized in ice-cold Tissue-Tearor (Biospec).…”

Section: Methodsmentioning

confidence: 99%

Budlein A, a Sesquiterpene Lactone From Viguiera robusta, Alleviates Pain and Inflammation in a Model of Acute Gout Arthritis in Mice

et al. 2018

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Background: Gout is the most common inflammatory arthritis worldwide. It is a painful inflammatory disease induced by the deposition of monosodium urate (MSU) crystals in the joints and peri-articular tissues. Sesquiterpene lactones (SLs) are secondary metabolite biosynthesized mainly by species from the family Asteraceae. It has been demonstrated that SLs present anti-inflammatory, analgesic, antitumoral, antiparasitic, and antimicrobial activities. In this study, we aimed at evaluating the efficacy of the SL budlein A in a model of acute gout arthritis in mice.Methods: Experiments were conducted in male Swiss or male LysM-eGFP mice. Animals were treated with budlein A (1 or 10 mg/kg) or vehicle 30 min before stimulus with MSU (100 μg/10 μL, intra-articular). Knee joint withdrawal threshold and edema were evaluated using electronic von Frey and caliper, respectively, 1–15 h after MSU injection. Leukocyte recruitment was determined by counting cells (Neubauer chamber), H&E staining, and using LysM-eGFP mice by confocal microscopy. Inflammasome components, Il-1β, and Tnf-α mRNA expression were determined by RT-qPCR. IL-1β and TNF-α production (in vitro) and NF-κB activation (in vitro and in vivo) were evaluated by ELISA. In vitro analysis using LPS-primed bone marrow-derived macrophages (BMDMs) was performed 5 h after stimulation with MSU crystals. For these experiments, BMDMs were either treated or pre-treated with budlein A at concentrations of 1, 3, or 10 μg/mL.Results: We demonstrated that budlein A reduced mechanical hypersensitivity and knee joint edema. Moreover, it reduced neutrophil recruitment, phagocytosis of MSU crystals by neutrophils, and Il-1β and Tnf-α mRNA expression in the knee joint. In vitro, budlein A decreased TNF-α production, which might be related to the inhibition of NF-κB activation. Furthermore, budlein A also reduced the IL-1β maturation, possibly by targeting inflammasome assembly in macrophages.Conclusion: Budlein A reduced pain and inflammation in a model of acute gout arthritis in mice. Therefore, it is likely that molecules with the ability of targeting NF-κB activation and inflammasome assembly, such as budlein A, are interesting approaches to treat gout flares.

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Differential regulation of oxidative stress and cytokine production by endothelin ET_A and ET_B receptors in superoxide anion-induced inflammation and pain in mice

Cited by 13 publications

References 68 publications

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice

Budlein A, a Sesquiterpene Lactone From Viguiera robusta, Alleviates Pain and Inflammation in a Model of Acute Gout Arthritis in Mice

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Differential regulation of oxidative stress and cytokine production by endothelin ETA and ETB receptors in superoxide anion-induced inflammation and pain in mice

Cited by 13 publications

References 68 publications

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

Trans-Chalcone Attenuates Pain and Inflammation in Experimental Acute Gout Arthritis in Mice

Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice

Budlein A, a Sesquiterpene Lactone From Viguiera robusta, Alleviates Pain and Inflammation in a Model of Acute Gout Arthritis in Mice

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Differential regulation of oxidative stress and cytokine production by endothelin ET_A and ET_B receptors in superoxide anion-induced inflammation and pain in mice