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Journal ArticleDOI

Protection from renal ischemia-reperfusion injury by the 2-methylaminochroman U83836E

01 Sep 1998-Kidney International (Nature Publishing Group)-Vol. 54, Iss: 3, pp 857-863
TL;DR: There is a protective effect of U83836E in ischemia-reperfusion injury, in that tissue damage due to oxidative stress is reduced, thus ameliorating renal function impairment.
About: This article is published in Kidney International.The article was published on 1998-09-01 and is currently open access. It has received 27 citations till now. The article focuses on the topics: Kidney & Kidney disease.
Citations
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Journal ArticleDOI
TL;DR: Evidence indicating that the inordinate or aberrant generation of reactive oxygen species (ROS) may contribute to the initiation and maintenance of ATN is reviewed, and the possibility that ROS may participate in the recovery phase of ATn is raised.

402 citations

Journal ArticleDOI
TL;DR: Treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction, suggesting that it may protect against ischemic renal injury.
Abstract: The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury.

254 citations

Journal ArticleDOI
TL;DR: The results suggest that resveratrol reduced the renal ischemia reperfusion injury through a nitric oxide-dependent mechanism.
Abstract: Reactive oxygen species have been implicated in the pathophysiology of renal ischemia reperfusion injury. Antioxidants including polyphenolics have been found to protect renal cells from the cellular injury induced by ischemia and reperfusion. Resveratrol, a stilbene polyphenol found in grapes and red wine, has recently been found to protect isolated rat heart from ischemia reperfusion injury. This study was sought to determine if resveratrol could also protect renal cells from ischemic injury. Male Wistar rats were treated with control, resveratrol (0.23 microg/kg), vehicle used to solubilize resveratrol, and resveratrol plus L-NAME (15 mg/kg body wt), a nitric oxide blocker. Our results demonstrated that resveratrol administration reduced the mortality of ischemic rats from 50% to 10% and renal damage was reduced as indicated by histologic examination and serum creatinine level. The short-term administration of resveratrol also inhibited renal lipid peroxidation induced by ischemia and reperfusion both in cortex and in medulla. Electron paramagnetic resonance detected an increased formation of nitric oxide in the resveratrol-treated kidney that was reduced to the baseline value after treating the rats with L-NAME in addition to resveratrol. The results suggest that resveratrol reduced the renal ischemia reperfusion injury through a nitric oxide-dependent mechanism.

151 citations

Journal ArticleDOI
TL;DR: The data clearly demonstrate that oxidative stress and RNS generation occur in the kidney during ischemia, and indicates that reactive nitrogen species (RNS) formation during I-R injury is driven by oxidant stress.

106 citations


Cites background from "Protection from renal ischemia-repe..."

  • ...The ability of superoxide dismutase (SOD), allopurinol, deferoxamine, and other antioxidants to attenuate renal I-R injury suggests that reactive oxygen species contribute to the development of renal injury (De Vecchi et al., 1998; Paller and Hedlund, 1988; Palleret al., 1984)....

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Journal ArticleDOI
TL;DR: Rats supplemented with DHEA and subjected to I/R had reduced pro-oxidant state, oxidative damage, and improved renal functionality, indicating an attenuation of oxidative injury and dysfunctions mediated by I-R.

102 citations


Cites background from "Protection from renal ischemia-repe..."

  • ...This protective effect may be related to the ability of antioxidant compounds to normalize early intracellular events linked to the progression of oxidative damage [8, 9]....

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References
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Journal ArticleDOI
01 Nov 1988-Stroke
TL;DR: U74006F- treated dogs survived significantly longer than vehicle-treated dogs, with significantly better neurologic function 1, 2, and 24 hours after arrest, and Vitamin E concentrations were significantly higher in the plasma of U74006f-treated Dogs 2, 3, and 6 hours after Arrest compared with vehicle-treatment dogs.
Abstract: The oxygen free radical-induced lipid peroxidative reactions that occur during resuscitation from normothermic cardiac arrest may contribute to the degree of neurologic dysfunction sustained. A blinded, randomized experimental trial was performed to determine whether U74006F, a potent inhibitor of lipid peroxidation, reduces morbidity and 24-hour mortality after 10 minutes of normothermic cardiopulmonary arrest; ventricular fibrillation was induced by electrical stimulation in 24 open-chest, halothane-anesthetized dogs, and circulation was reestablished by direct cardiac compressions, administration of a standardized drug regime, and internal countershocks. When spontaneous circulation was restored, a bolus injection of 1.5 mg/kg U74006F (n = 12) or 25 mM citrate vehicle (n = 12) was infused intravenously in 15 minutes and an infusion was continued at 0.125 mg/kg/hr for the next 12 hours. In the drug-treated group, plasma U74006F concentration averaged 0.13 microgram/ml between 3 and 12 hours after cardiac arrest. By 24 hours after arrest, 10 of 12 (83%) vehicle-treated dogs had died but only four of 12 (33%) U74006F-treated dogs had died (p = 0.017). U74006F-treated dogs survived significantly longer (mean +/- SEM 22 +/- 1 hr) than vehicle-treated dogs (18 +/- 1 hr), with significantly better neurologic function 1, 2, and 24 hours after arrest. Plasma fatty acid hydroperoxide concentrations 12 hours after arrest were 88 +/- 81 pmol/ml in U74006F-treated and 241 +/- 49 pmol/ml in vehicle-treated dogs (p less than 0.05). Vitamin E concentrations were significantly higher in the plasma of U74006F-treated dogs 2, 3, and 6 hours after arrest compared with vehicle-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

98 citations

Journal ArticleDOI
TL;DR: Findings indicate that a new 21-aminosteroid with in vitro antioxidant and antilipolytic properties prevents the SAH-induced chronic vasospasm in this model by limiting these pathological membrane events.
Abstract: ✓ The purpose of this study was to use a new 21-aminosteroid (U-74006F) with in vitro antioxidant and antilipolytic properties as a pharmacological probe to assess the role of lipid hydrolysis and peroxidation in a rabbit model of subarachnoid hemorrhage (SAH)-induced vasospasm. Cerebral angiograms were performed on 15 rabbits. Eighteen hours later, 1 cc/kg of autologous blood was infused into the cisterna magna of all 15 animals. Six rabbits received no treatment, six received U-74006F starting 30 minutes after SAH, and three rabbits received the vehicle for U-74006F starting 30 minutes after SAH. At 72 hours post-SAH, a second angiogram was obtained. Digital subtraction angiographic techniques were used to measure the diameter of and contrast material flow through the basilar artery. At 72 hours post-SAH, vasospasm was evident in all untreated and vehicle-treated rabbits. The diameter of and the flow through the basilar artery were significantly reduced 42.3% ± 6.6% and 46.8% ± 5.8%, respectively, below...

94 citations

Journal ArticleDOI
TL;DR: This HPLC assay with o-phthalaldehyde precolumn derivatization is used to measure the total, oxidized, and protein-bound forms of glutathione in human blood, plasma, and rat tissue and showed high sensitivity and good precision.
Abstract: This HPLC assay with o-phthalaldehyde precolumn derivatization is used to measure the total, oxidized, and protein-bound forms of glutathione in human blood, plasma, and rat tissue. Total glutathione (i.e., sum of reduced, oxidized, and protein-bound fractions) was determined after reduction with dithiothreitol and protein precipitation with perchloric acid (PCA). A preliminary selective blockage of free sulfhydryl groups with N-ethylmaleimide was necessary to evaluate the different oxidized forms. The assay showed high sensitivity ( 0.999). Samples, after PCA acidification, were stable at room temperature and 4 degrees C for 3 days, and at -20 degrees C and -80 degrees C for > 1 month. The method (involving automated derivatization) not only is very rapid and simple but also allows immediate processing of many different biological samples.

90 citations


"Protection from renal ischemia-repe..." refers methods in this paper

  • ...After centrifugation (10,000 3 g at 4°C, 1 min) of the acidic homogenate, total and oxidized soluble glutathione were determined by a reversed-phase high pressure liquid chromatography (HPLC) method, as described by Paroni et al [19]....

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  • ...After centrifugation (10,000 3 g at 4°C, 1 min) of the acidic homogenate, total and oxidized soluble glutathione were determined by a reversed-phase high pressure liquid chromatography (HPLC) method, as described by Paroni et al [19]....

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Journal ArticleDOI
Edward D. Hall1
TL;DR: A novel series of potent lipid peroxidation inhibitors known as the 21‐aminosteroids or “lazaroids" have been developed and shown efficacy in animal models of brain injury and focal cerebral ischemia and to be effective in decreasing the clinical disease severity and blood‐brain barrier disruption observed in the multiple sclerosis model of experimental allergic encephalomyelitis.
Abstract: A considerable body of information supports the occurrence and pathophysiological importance of oxygen radical-mediated lipid peroxidation in acute cerebral damage secondary to traumatic or ischemic injury. Moreover, peroxidative mechanisms have been implicated in chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases) and demyelinating (e.g., multiple sclerosis) disorders. Consequently, there has been interest in identification of pharmacological agents with potent ability to interrupt oxygen radical formation or cell membrane lipid peroxidative mechanisms. Our laboratories have developed a novel series of potent lipid peroxidation inhibitors known as the 21-aminosteroids or "lazaroids." One of these compounds, U-74006F or tirilazad mesylate, has shown efficacy in animal models of brain injury and focal cerebral ischemia. In addition, the compound has been found to attenuate the increased lipid peroxidation observed in Alzheimer's brain tissue, to retard anterograde degeneration of motor nerve fibers, and to be effective in decreasing the clinical disease severity and blood-brain barrier disruption observed in the multiple sclerosis model of experimental allergic encephalomyelitis. Another series of antioxidants, the 2-methylaminochromans typified by the compound U-78517F, have been discovered that are even more potent and effective inhibitors of lipid peroxidation than the 21-aminosteroids.

87 citations


"Protection from renal ischemia-repe..." refers background in this paper

  • ...more than tenfold that of the first generation lazaroids [12]....

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Journal ArticleDOI
TL;DR: It is suggested that oxidative stress plays an important role in the death of cultured embryonic dopamine neurones and that lazaroids may be potent neuroprotective agents in situations where dopaminergic neurones degenerate.
Abstract: We have studied the effects of two lazaroids, U-74389G and U-83836E, on the survival of cultured rat dopamine neurones. Lazaroids are inhibitors of free radical formation and lipid peroxidation. Dissociated embryonic mesencephalic neurones were cultivated for 2 or 7 days under serum-free conditions with or without the addition of 0.3 microM of one of the lazaroids. Both lazaroids enhanced the survival of tyrosine hydroxylase immunoreactive, dopaminergic neurones both after 2 and 7 days in vitro to around 111-120% and 175-180% of controls, respectively. Since the total number of neurones was also increased following lazaroid treatment, it is unlikely that lazaroids exert their effects on only dopamine neurones. These findings suggest that oxidative stress plays an important role in the death of cultured embryonic dopamine neurones and that lazaroids may be potent neuroprotective agents in situations where dopaminergic neurones degenerate.

53 citations


Additional excerpts

  • ...lated calcium influx have been reported [17, 18]....

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