Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO−cGMP−PKG−KATPChannel Signaling Pathway

Manchope, Marília F.; Calixto-Campos, Cássia; Coelho-Silva, Leticia; Zarpelon, Ana C.; Pinho‐Ribeiro, Felipe A.; Georgetti, Sandra R.; Baracat, Marcela M.; Casagrande, Rúbia; Verri, Waldiceu A.

doi:10.1371/journal.pone.0153015

Cited by 117 publications

(89 citation statements)

References 74 publications

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“…The red arrows represent endogenous pathways that are inhibited by flavonoids resulting in reduced pain and inflammation. , NF-κB [51] and Nrf2 [52], Quercetin: MAPK [53], NF-κB [53][54][55], AKT [56], Nrf2 [33,54], and NLRP3 [57] and Naringenin: NF-κB [58][59][60] and Nrf2 [59,61,62]. (B) Ion channels expressed by neurons that are targeted by Vitexin, Quercetin, and Naringenin to reduce pain.…”

Section: Pre-clinical Evidence Of Flavonoids For Pain Controlmentioning

confidence: 99%

“…Its effects on inflammation have been demonstrated in UVB irradiation [61,124], inflammatory pain [58,62,125], and arthritis [59]. The mechanisms by which naringenin reduces inflammation and pain are related to inhibition of oxidative stress [61,62,124,126], leukocyte recruitment [59,60], MPO activity [124,127], NF-κB activation [58][59][60], mRNA expression of inflammasome components [59], pro-inflammatory cytokine production (TNF-α, IL-1β, IL-33, IL-6, IFN-γ, IL-12, IL-4, IL-5, IL-13, IL-17, and IL-22) [58][59][60]62,124,125,127], and MAPK signaling activation [128]. In addition, naringenin modulates macrophages activation [129] and microbicidal activity of neutrophils [130], and reduces DC maturation [131].…”

Section: Flavanonesmentioning

confidence: 99%

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Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

et al. 2020

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Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (-OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation.

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Section: Pre-clinical Evidence Of Flavonoids For Pain Controlmentioning

confidence: 99%

Section: Flavanonesmentioning

confidence: 99%

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

et al. 2020

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“…Nevertheless, naringenin also modulates TRP channels such as TRVP1, TRPM3 and TRPM8 reducing pain [7], and activates a NO signaling pathway that induces nociceptor neuron hyperpolarization [2, 3]. Therefore, naringenin treatment is a promising analgesic, anti-inflammatory and antioxidant compound, requiring further investigation in preclinical models and clinical settings.…”

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confidence: 99%

Naringenin: an analgesic and anti-inflammatory citrus flavanone

2016

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“…KO 2 reduces Nrf2 mRNA expression and drugs that enhance Nrf2 mRNA expression inhibit KO 2 -induced pain [34]. Thus, the effect of tempol in KO 2 -induced reduction of Nrf2 mRNA expression was investigated.…”

Section: Resultsmentioning

confidence: 99%

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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Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO−cGMP−PKG−KATPChannel Signaling Pathway

Cited by 117 publications

References 74 publications

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

Naringenin: an analgesic and anti-inflammatory citrus flavanone

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

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