A Novel Free Radical Scavenger, Edarabone, Protects Against Cisplatin-Induced Acute Renal Damage in Vitro and in Vivo

Satoh, Minoru; Kashihara, Naoki; Fujimoto, Sohachi; Horike, Hideyuki; Tokura, Takehiko; Namikoshi, Tamehachi; Sasaki, Tatsuya; Makino, Hírofumi

doi:10.1124/jpet.102.047522

Cited by 138 publications

(116 citation statements)

References 34 publications

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“…Moreover, edaravone reduced mitochondrial damage in homogenate made from ischemic-incubated rat brain (Watanabe et al 1994). As compared with other antioxidants, edaravone has the following advantages: (1) it has already been used in clinical practice mostly without the presence of serious side effects at the dose currently applied (Sueishi et al 2002); (2) it is lipophilic, and therefore, readily accessible to tissues (Satoh et al 2003); (3) it preferentially accumulates in the kidneys (Spitz et al 2011). This accumulation in the kidneys is desirable because it presumably confers some selectivity towards the healthy tissue and favors nephroprotection.…”

Section: Discussionmentioning

confidence: 99%

Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage

Chen

Liu

Dong

et al. 2015

Cell Stress and Chaperones

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Radiation-induced cellular injury is attributed primarily to the harmful effects of free radicals, which play a key role in irradiation-induced apoptosis. In this study, we investigated the radioprotective efficacy of edaravone, a licensed clinical drug and a powerful free radical scavenger that has been tested against γ-irradiation-induced cellular damage in cultured human peripheral blood lymphocytes in studies of various diseases. Edaravone was pre-incubated with lymphocytes for 2 h prior to γ-irradiation. It was found that pretreatment with edaravone increased cell viability and inhibited generation of γ-radiation-induced reactive oxygen species (ROS) in lymphocytes exposed to 3 Gy γ-radiation. In addition, γ-radiation decreased antioxidant enzymatic activity, such as superoxide dismutase and glutathione peroxidase, as well as the level of reduced glutathione. Conversely, treatment with 100 μM edaravone prior to irradiation improved antioxidant enzyme activity and increased reduced glutathione levels in irradiated lymphocytes. Importantly, we also report that edaravone reduced γ-irradiation-induced apoptosis through downregulation of Bax, upregulation of Bcl-2, and consequent reduction of the Bax:Bcl-2 ratio. The current study shows edaravone to be an effective radioprotector against γ-irradiation-induced cellular damage in lymphocytes in vitro. Finally, edaravone pretreatment significantly reduced DNA damage in γ-irradiated lymphocytes, as measured by comet assay (% tail DNA, tail length, tail moment, and olive tail moment) (p<0.05). Thus, the current study indicates that edaravone offers protection from radiation-induced cytogenetic alterations.

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Section: Discussionmentioning

confidence: 99%

Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage

Chen

Liu

Dong

et al. 2015

Cell Stress and Chaperones

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“…Cytochrome c oxidase is a large transmembrane protein that acts as a terminal acceptor in the electron transport chain. It is one of the key enzymes modulating mitochondrial functions, and its activity was assessed by enzyme histochemical method (8). Strong cytochrome c oxidase activity (brown) was observed to be widely expressed in the renal cortex, mainly in the tubular epithelium, in control group of mice (Fig.…”

Section: Amelioration Of Renal Injury and Extended Life Span By Klothmentioning

confidence: 99%

“…8. Semiquantitative analysis was performed by viewing random areas at a magnification of ϫ100 and scored for the number of apoptotic nuclei present in renal tissues.…”

Section: Assessment Of Apoptosismentioning

confidence: 99%

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Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Haruna

Kashihara

Satoh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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224

212

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Klotho, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the Klotho gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the Klotho transgene (ICGN), ICGN mice with the Klotho transgene (ICGN/klTG), wild-type mice with the Klotho transgene (klTG), and wild-type mice without the Klotho transgene (control). At 40 weeks old, the survival rate was Ϸ30% in ICGN mice, and Ϸ70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome c oxidase activity but a reduction in ␤-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although Klotho is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.aging ͉ glomerulonephritis ͉ oxidative stress ͉ tubular interstitial disease T he Klotho gene was originally identified by insertional mutagenesis, and it encodes a 130-kDa transmembrane protein that shares sequence homology with ␤-glucosidase (1). The gene is predominantly expressed in the kidney and, to a lesser extent, in the brain and reproductive and endocrine organs. Its deletion in mice (Kl Ϫ/Ϫ ) results in the development of a syndrome resembling human aging, including shortened life span, growth retardation, infertility, arteriosclerosis, skin and muscle atrophy, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the Klotho gene extends the life span in mice (2). Although kl Ϫ/Ϫ mice do not show any overt renal abnormalities, the Klotho mRNA expression in the kidneys has been shown to be greatly reduced in patients with chronic renal failure (3). Notably, most of the features of Klotho gene-deleted mice are similar to those of the patients with chronic renal failure. In addition, Klotho gene expression has been found to be reduced in acute renal failure in ischemia-reperfusion injury murine models (4). These findings would imply that the reduction of Klotho protein may be relevant to the pathophysiology of renal failure. However, little is known concerning whether Klotho protein itself could exert an ameliorative effect on a diseased kidney to preserve its renal functions and thus could serve as a therapeutic target in various ...

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“…11 The percent positive area was measured with a color image analyzer. A total of 20 consecutive fields from each kidney were evaluated randomly at a magnification of Â 100.…”

Section: Cytochrome C Oxidase (Cox) Stainingmentioning

confidence: 99%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

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A Novel Free Radical Scavenger, Edarabone, Protects Against Cisplatin-Induced Acute Renal Damage in Vitro and in Vivo

Cited by 138 publications

References 34 publications

Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage

Edaravone protects human peripheral blood lymphocytes from γ-irradiation-induced apoptosis and DNA damage

Amelioration of progressive renal injury by genetic manipulation of Klotho gene

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

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