Evaluation of edaravone against radiation-induced oral mucositis in mice

Nakajima, N.; Watanabe, Shinichi; Kiyoi, Takeshi; Tanaka, Akihiro; Suemaru, Katsuya; Araki, Hiroaki

doi:10.1016/j.jphs.2015.02.001

Cited by 26 publications

(24 citation statements)

References 19 publications

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“…Since neutrophil recruitment is normally compromised in mice deficient in IL-17RA we next asked if the neutrophils in the lesion were functionally competent in Il17ra −/− mice. We measured myeloperoxidase (MPO) levels in tongue, a parameter also commonly used to assess the severity of OM (8,45,46). The oral mucosa of irradiated Il17ra −/− mice had greater MPO production compared to irradiated WT mice on Day 11 aligning with the increased presence of neutrophils in Il17ra −/− mice (Figure 4E).…”

Section: Enhanced Neutrophil Response In Il-17ra-deficient Micementioning

confidence: 86%

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

et al. 2021

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Oral mucositis (OM) is a treatment-limiting adverse side effect of radiation and chemotherapy. Approximately 80% of patients undergoing radiotherapy (RT) for head and neck cancers (HNC) develop OM, representing a major unmet medical condition. Our understanding of the immunopathogenesis of OM is limited, due in part to the surprising paucity of information regarding healing mechanisms in the oral mucosa. RNAseq of oral tissue in a murine model that closely mimics human OM, showed elevated expression of IL-17 and related immune pathways in response to head and neck irradiation (HNI). Strikingly, mice lacking the IL-17 receptor (IL-17RA) exhibited markedly more severe OM. Restoration of the oral mucosa was compromised in Il17ra−/− mice and components associated with healing, including matrix metalloproteinase 3, 10 and IL-24 were diminished. IL-17 is typically associated with recruitment of neutrophils to mucosal sites following oral infections. Unexpectedly, in OM the absence of IL-17RA resulted in excessive neutrophil recruitment and immunopathology. Instead, neutrophil activation was IL-1R-driven in Il17ra−/− mice. Blockade of IL-1R and depletion of neutrophils lessened the severity of damage in these mice. Overall, we show IL-17 is protective in OM through multiple mechanisms including restoration of the damaged epithelia and control of the neutrophil response. We also present a clinically relevant murine model of human OM to improve mechanistic understanding and develop rational translational therapeutics.

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Section: Enhanced Neutrophil Response In Il-17ra-deficient Micementioning

confidence: 86%

Tissue Damage in Radiation-Induced Oral Mucositis Is Mitigated by IL-17 Receptor Signaling

et al. 2021

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“…In the first part, rats were allocated to five groups ( n = 8 per group): sham (Sham), cecal ligation and puncture (CLP), and low (CLP + L-EDA), medium (CLP + M-EDA), or high dose (CLP + H-EDA) of the edaravone group. Rats were infused slowly with saline (2 mL) or 50 (low), 100 (medium), 200 (high) mg/kg edaravone [ 22 ] 10 minutes before CLP. In the second part, rats were allocated to four groups ( n = 8 per group): Sham, CLP, CLP + H-EDA, and CLP + H-EDA+ 2-methoxyestradiol (ME).…”

Section: Methodsmentioning

confidence: 99%

Edaravone Improves Septic Cardiac Function by Inducing an HIF‐1α/HO‐1 Pathway

Zhang

et al. 2018

Oxidative Medicine and Cellular Longevity

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Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.

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“…Although pharmacological and non-pharmacological therapies were applied for RIOM, yet, no single therapy was identified to significantly minimize and/or repair RIOM. Such expected significant therapeutic benefit would be mediated through reducing the injury severity and duration to a clinically relevant extent [2,4,5,12,. The inflammatory nature of the RIOM directs the current studies towards finding a convenient antiinflammatory therapy for such tissue injury.…”

Section: The 2 Nd Manuscript Contributions Were As Followsmentioning

confidence: 99%