The flavonoid vitexin (1) is a flavone C-glycoside (apigenin-8-C-β-d-glucopyranoside) present in several medicinal and other plants. Plant extracts containing 1 are reported to possess ...antinociceptive, anti-inflammatory, and antioxidant activities. However, the only evidence that 1 exhibits antinociceptive activity was demonstrated in the acetic acid-induced writhing model. Therefore, the analgesic effects and mechanisms of 1 were evaluated. In the present investigation, intraperitoneal treatment with 1 dose-dependently inhibited acetic acid-induced writhing. Furthermore, treatment with 1 also inhibited pain-like behavior induced by phenyl-p-benzoquinone, complete Freund’s adjuvant (CFA), capsaicin (an agonist of transient receptor potential vanilloid 1, TRPV1), and both phases of the formalin test. It was also observed that inhibition of carrageenan-, capsaicin-, and chronic CFA-induced mechanical and thermal hyperalgesia occurred. Regarding the antinociceptive mechanisms of 1, it prevented the decrease of reduced glutathione levels, ferric-reducing ability potential, and free-radical scavenger ability, inhibited the production of hyperalgesic cytokines such as TNF-α, IL-1β, IL-6, and IL-33, and up-regulated the levels of the anti-hyperalgesic cytokine IL-10. These results demonstrate that 1 exhibits an analgesic effect in a variety of inflammatory pain models by targeting TRPV1 and oxidative stress and by modulating cytokine production.
Background and Purpose
Maresin 1 (MaR1) is a specialised pro‐resolving lipid mediator with anti‐inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and ...spinal cord cells by MaR1 in the context of inflammatory pain.
Experimental Approach
Mice were treated with MaR1 before intraplantar injection of carrageenan or complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed using the electronic von Frey and thermal hyperalgesia using a hot plate. Spinal cytokine production and NF‐κB activation were determined by ELISA and astrocytes and microglia activation by RT‐qPCR and immunofluorescence. CGRP release by dorsal root ganglia (DRG) neurons was determined by EIA. Neutrophil and macrophage recruitment were determined by immunofluorescence, flow cytometry, and colorimetric methods. Trpv1 and Nav1.8 expression and calcium imaging of DRG neurons were determined by RT‐qPCR and Fluo‐4AM respectively.
Key Results
MaR1 reduced carrageenan‐ and CFA‐induced mechanical and thermal hyperalgesia and neutrophil and macrophage recruitment proximal to CGRP+ fibres in the paw skin. Moreover, MaR1 reduced NF‐κB activation, IL‐1β and TNF‐α production, and spinal cord glial cells activation. In the DRG, MaR1 reduced CFA‐induced Nav1.8 and Trpv1 mRNA expression and calcium influx and capsaicin‐induced release of CGRP by DRG neurons.
Conclusions and Implications
MaR1 reduced DRG neurons activation and CGRP release explaining, at least in part, its analgesic and anti‐inflammatory effects. The enduring analgesic and anti‐inflammatory effects and also post‐treatment activity of MaR1 suggest that specialised pro‐resolving lipid mediators have potential as a new class of drugs for the treatment of inflammatory pain.
Neutrophil infiltration, pro-inflammatory cytokines, and reactive oxygen species (ROS) production have been implicated in development and progression of ulcerative colitis (UC), an inflammatory bowel ...disease (IBD) characterized by ulcerating inflammation of the mucosal layer generally restricted to the colon. The side effects, safety and human intolerance are limitations of the currently approved treatments for UC. Hesperidin methyl chalcone (HMC) is a flavonoid used to treat chronic venous disease, which shows anti-inflammatory, analgesic, and antioxidant properties in pre-clinical studies, however, its effects on colitis have never been described. Therefore, we aimed to evaluate the protective effects of HMC in a mouse model of acetic acid-induced colitis. Treatment with HMC significantly reduced neutrophil infiltration, edema, colon shortening, macro and microscopic damages induced by intracolonic administration of acetic acid. The improvement of colitis after HMC treatment is related to the increase in colon antioxidant status, and the inhibition of pro-inflammatory cytokines TNF-α, IL-6, IL-1β, and IL-33 in the colon. We observed, moreover, that HMC inhibited NF-κB activation in the colon, which might explain the reduction of the cytokines we observed. Finally, these results demonstrate a novel applicability of HMC to increase antioxidant response and reduce inflammation during acetic acid-induced colitis suggesting it as a promising therapeutic approach for the treatment of ulcerative colitis.
•Methylation of hesperidin produces hesperidin methyl chalcone (HMC).•HMC inhibited neutrophil infiltration, edema and colon shortening in mouse colitis.•HMC also inhibited macroscopic and microscopic damages in colitis.•HMC reduced oxidative stress, cytokine production and NF-κB activation.•This is the first study demonstrating that HMC treats experimental ulcerative colitis.
The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed ...onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase CK blood levels and myoblast determination protein MyoD mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein GFAP and ionized calcium-binding adapter molecule 1 Iba-1 mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise.
IL-33/ST2 signaling boosts inflammation and pain Fattori, Victor; Borghi, Sergio M.; Verri, Waldiceu A.
Proceedings of the National Academy of Sciences,
11/2017, Letnik:
114, Številka:
47
Journal Article
Lipopolysaccharide (LPS) is the major structural component of Gram-negative bacteria cell wall and a highly pro-inflammatory toxin. Naringenin is found in Citrus fruits and exhibits antioxidant and ...anti-inflammatory properties through inhibition of NF-κB activation but its effects in LPS-induced inflammatory pain and leukocyte recruitment were not investigated yet. We investigated the effects of naringenin in mechanical hyperalgesia, thermal hyperalgesia and leukocyte recruitment induced by intraplantar injection of LPS in mice. We found that naringenin reduced hyperalgesia to mechanical and thermal stimuli, myeloperoxidase (MPO, a neutrophil and macrophage marker) and N-acetyl-β-D-glucosaminidase (NAG, a macrophage marker) activities, oxidative stress and cytokine (TNF-α, IL-1β, IL-6, and IL-12) production in the paw skin. In the peritoneal cavity, naringenin reduced neutrophil and mononuclear cell recruitment, and abrogated MPO and NAG activity, cytokine and superoxide anion production, and lipid peroxidation. In vitro, pre-treatment with naringenin inhibited superoxide anion and cytokine (TNF-α, IL-1β, IL-6, and IL-12) production by LPS-stimulated RAW 264.7 macrophages. Finally, we demonstrated that naringenin inhibited NF-κB activation in vitro and in vivo. Therefore, naringenin is a promising compound to treat LPS-induced inflammatory pain and leukocyte recruitment.
Maresin-2 (MaR2) is a specialized pro-resolution lipid mediator (SPM) that reduces neutrophil recruitment in zymosan peritonitis. Here, we investigated the analgesic effect of MaR2 and its mechanisms ...in different mouse models of pain. For that, we used the lipopolysaccharide (LPS)-induced mechanical hyperalgesia (electronic version of the von Frey filaments), thermal hyperalgesia (hot plate test) and weight distribution (static weight bearing), as well as the spontaneous pain models induced by capsaicin (TRPV1 agonist) or AITC (TRPA1 agonist). Immune cell recruitment was determined by immunofluorescence and flow cytometry while changes in the pro-inflammatory mediator landscape were determined using a proteome profiler kit and ELISA after LPS injection. MaR2 treatment was also performed in cultured DRG neurons stimulated with capsaicin or AITC in the presence or absence of LPS. The effect of MaR2 on TRVP1- and TRPA1-dependent CGRP release by cultured DRG neurons was determined by EIA. MaR2 inhibited LPS-induced inflammatory pain and changes in the cytokine landscape as per cytokine array assay. MaR2 also inhibited TRPV1 and TRPA1 activation as observed by a reduction in calcium influx in cultured DRG neurons, and the number of flinches and time spent licking the paw induced by capsaicin or AITC. In corroboration, MaR2 reduced capsaicin- and AITC-induced CGRP release by cultured DRG neurons and immune cell recruitment to the paw skin close the CGRP+ fibers. In conclusion, we show that MaR2 is an analgesic SPM that acts by targeting leukocyte recruitment, nociceptor TRPV1 and TRPA1 activation, and CGRP release in mice.
•Maresin-2 (MaR2) reduces pain and inflammation caused by the microbial product LPS.•MaR2 reduces TRPV1 and TRPA1 activation in mouse dorsal root ganglion (DRG) neurons.•MaR2 reduces pain-like behavior triggered by TRPV1 and TRPA1 agonists.•MaR2 inhibits CGRP release by mouse DRG neurons.•MaR2 reduces recruitment of CD11b+ cells close to CGRP + nociceptors.
Neuroinflammatory diseases that affect spinal cord or associated spinal nerves represent challenging conditions for management in current medicine because of their complex pathology, poor prognosis, ...and high morbidity, which strikingly reduces the quality of life of patients. In this sense, a better understanding of the cellular and molecular mechanisms of spinal cord neuroinflammation might contribute to the development of novel therapies. Oligodendrocytes have unique and vital biological properties in central nervous system (CNS) homeostasis and physiology. A growing body of experimental evidence demonstrates that these glial cells are involved in the pathophysiological mechanisms underlying many chronic, neurodegenerative, and incapacitating CNS disorders. These cells also have important implications for the development and maintenance of neural plasticity and chronic pain states. On the other hand, evidence indicates that oligodendrocytes and their products may act in favor of CNS promoting beneficial effects orchestrating CNS tissue repair after injury.
The present review aims to explore the multi-faceted actions of spinal cord oligodendrocyte progenitors cells (OPCs) and mature oligodendrocytes in CNS inflammation and pathology, addressing their roles in experimental and clinical settings. A major focus was given to spinal cord amyotrophic lateral sclerosis, multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), traumatic injury and pain processing.
This review analyses and discusses published original research articles regarding the role of OPCs/oligodendrocytes in spinal cord inflammation and pain processing.
Findings from a number of clinical and experimental paradigms suggest spinal cord OPCs/oligodendrocytes are a potential therapeutic target for the control of neuroinflammation.
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.
-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
-Chalcone in experimental gout arthritis in mice. Mice were treated with
-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
-Chalcone inhibited MSU-induced mechanical hyperalgesia, edema, and leukocyte recruitment (total leukocytes, neutrophils, and mononuclear cells) in a dose-dependent manner.
-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.
-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
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,
-Chalcone reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and thereby the mRNA expression of the inflammasome components
(cryopyrin),
(apoptosis-associated speck-like protein containing a CARD),
and
.
,
-Chalcone reduced the MSU-induced release of IL-1β in lipopolysaccharide (LPS)-primed macrophages. Therefore, the pharmacological effects of
-Chalcone indicate its therapeutic potential as an analgesic and anti-inflammatory flavonoid for the treatment of gout.
Sphagneticola trilobata (L.) Pruski is used in traditional medicine in Brazil for inflammatory diseases treatment including asthma. The diterpene kaurenoic acid (KA) is one of its active compounds, ...but whether KA activity could explain the traditional use of S. trilobata in asthma is unknown.
Investigate KA effect and mechanisms in asthma.
Experimental asthma was induced by ovalbumin immunization and challenge in male Swiss mice. KA (0.1–10 mg/kg, gavage) was administered 1 h before the ovalbumin challenge. Total leukocytes, eosinophil, and mast cell were counted in bronchoalveolar lavage fluid (BALF), and lung histopathology was performed. Lung mRNA expression of Th2 and regulatory T cells markers, and BALF type 2 cytokine production were quantitated. NFκB activation and oxidative stress-related components in pulmonary tissue were measured.
KA inhibited the migration of total leukocytes and eosinophils to BALF, reduced lung histopathology (inflammatory cells and mast cells), mRNA expression of IL-33/ST2, STAT6/GATA-3 and NFκB activation in the lung, and reduced IL-33, IL-4, IL-5 production in the BALF. KA also reduced the mRNA expression of iNOS and gp91phox, and superoxide anion production accompanied by the induction of Nrf2, HO-1 and NQO1 mRNA expression, thus, exerting an antioxidant effect. Finally, KA induced nTreg-like and Tr1-like, but not Th3-like markers of suppressive T cell phenotypes in the lung tissue.
KA prevents antigen-induced asthma by down-regulating Th2 and NFκB/cytokine-related pathways, and up-regulating Nrf2 and regulatory T cells’ markers. Thus, explaining the ethnopharmacological use of S. trilobata for the treatment of lung inflammatory diseases.
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