potassium-ascorbyl-tocopheryl-phosphate and Disease-Models--Animal

As a non-toxic endogenous antioxidant, the semi-essential amino acid taurine is a potential attenuator of oxidative damage such as that produced by ischaemia-reperfusion injury. Ischaemia-reperfusion injury is a well established if paradoxical phenomenon whereby ischaemic tissue, doomed to necrosis if it is not reperfused, is actually further damaged by oxidative attack when perfusion is restored. This paper is a review of the literature concerning therapeutic strategies in ischaemia-reperfusion injury, including non-pharmacological and pharmacological interventions. There is consistent experimental evidence of an important role of taurine in ischaemia-reperfusion injury, with a clinical role emerging in human trials of taurine administered prior to coronary artery bypass grafting and heart valve surgery.

Topics: Animals; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Disease Models, Animal; Free Radical Scavengers; Free Radicals; Humans; Ischemic Preconditioning; Lipid Peroxidation; Reperfusion Injury; Taurine; Vitamin E

Acute kidney injury (AKI) occurs frequently in the intensive care unit. A primary cause is renal ischemia/reperfusion (I/R) injury, during which excess reactive oxygen species (ROS) are produced. ROS subsequently damage renal cells, leading to the development of AKI. Here, we investigated whether renal I/R injury could be attenuated by the antioxidant EPC-K1.. We divided male Wistar rats into the following three groups: (1) a renal I/R group, (2) an EPC-K1 + renal I/R group and (3) a control group. Rats were sacrificed 24 h after treatment (I/R or sham). To measure oxidative stress in renal tissue, histological examinations were performed and serum levels of blood urea nitrogen (BUN) and creatinine were measured. The antioxidant action of EPC-K1 was also evaluated in RAW264.7 cells stimulated with antimycin A.. Serum BUN and creatinine levels were elevated in the I/R group; however, this increase was significantly attenuated by EPC-K1 in the EPC-K1 + I/R group. Renal tissue injury was also significantly lower in the EPC-K1 + I/R group compared with the I/R group. In vitro experiments showed that EPC-K1 significantly attenuated the generation of ROS induced by antimycin A.. In our study, EPC-K1 was able to attenuate AKI due to renal I/R by reducing oxidative stress. These results suggest that EPC-K1 may be effective against various types of I/R injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Cell Line; Disease Models, Animal; Kidney; Kidney Diseases; Kidney Function Tests; Male; Malondialdehyde; Mice; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Vitamin E

Cerebral ischaemia-reperfusion injury is associated with the generation of reactive oxygen species during the early phases of reoxygenation. EPC-K1, a phosphate diester of vitamins C and E, has been reported to possess potent hydroxyl radical scavenging activity. This study was performed to investigate the effectiveness of EPC-K1 in attenuating cerebral ischaemia-reperfusion injury in a rat model of transient focal cerebral ischaemia.. We evaluated the efficacy of EPC-K1 by measuring the concentration of cerebral thiobarbituric acid reactive substances (TBARS), an indicator of the extent of lipid peroxidation by free radicals, and infarct size in rats subjected to one hour of cerebral ischaemia and 4, 24, or 72 hours of reperfusion.. EPC-K1 significantly reduced both the cerebral TBARS level and the infarct size in a rat model of transient focal cerebral ischaemia. These results indicate that EPC-K1 administration during the early stages of reperfusion ameliorates ischaemic brain injury by inhibiting lipid peroxidation.. This report is the first to describe the protective mechanism of EPC-K1 by measuring both the TBARS level and infarct size in a rat model of transient focal cerebral ischaemia, and may suggest a potential clinical approach for the treatment of ischaemic cerebrovascular disease.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain Ischemia; Disease Models, Animal; Free Radicals; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Vitamin E

We sought to investigate the effects of EPC-K1, a free radical scavenger, on reducing heparin-produced cerebral hemorrhage in a rabbit model of middle cerebral artery (MCA) photothrombosis and to investigate whether the combination of EPC-K1 and heparin enhances neuroprotection from cerebral ischemic damage.. In the heparin-alone group (n=8), heparin was administered intravenously for 24 hours, starting from 3 hours after MCA occlusion. In the EPC-K1-alone group (n=8), EPC-K1 was administered as a bolus injection (10 mg/kg) twice at 3 and 6 hours after MCA occlusion. In the combination group (n=8), EPC-K1 and heparin both were administered as in the single-drug procedures. In the vehicle group (n=10), saline were infused for 24 hours.. Heparin prolonged activated partial thromboplastin time by approximately 3 times that of control animals. In the heparin-treated animals, the hemorrhage size was significantly increased (P<0.0001) and neurological symptoms were significantly worse (P<0.01) than in control animals at 48 hours. The combination of EPC-K1 and heparin dramatically reduced heparin-produced cerebral hemorrhage (P<0.0001), with a significant reduction in infarct volume (reduction by 63.2% and 57.2% of heparin-alone and control animals, respectively, P<0.0001) and a significant improvement in neurological symptoms (P<0.01 versus heparin-alone and control animals, respectively).. These data indicate that free radical formation may play a key role in intracerebral hemorrhage exacerbated by heparin treatment and that the combination of a free radical scavenger and heparin augmented neuroprotection from acute brain ischemia. The results of the present study may suggest a potential clinical approach for the treatment of acute stroke.

Topics: Animals; Ascorbic Acid; Blood Flow Velocity; Body Temperature; Cerebral Hemorrhage; Disease Models, Animal; Drug Therapy, Combination; Free Radical Scavengers; Heparin; Infarction, Middle Cerebral Artery; Light Coagulation; Middle Cerebral Artery; Partial Thromboplastin Time; Rabbits; Reperfusion; Treatment Outcome; Vitamin E

Oxygen free radicals (OFR) and neutrophils are potent sources of reperfusion injury. We compared the effect of EPC-K1, a new OFR scavenger, and neutrophil depletion on the reperfusion injury in skeletal muscle, using an ischemic revascularized hindlimb model in rats. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 h. After 24 h of reperfusion, muscle function and damage were evaluated in 4 groups: a sham operation group, a control study group, a group treated by EPC-K1 (EPC group), and a group that received nitrogen mustard to induce neutropenia (NM group). Both the EPC and NM groups had limited muscle damage compared to the control group. The EPC group preserved muscle function significantly better than the control group and the mean isometric tetanic tension in the EPC group appeared to be higher than that in the NM group. Furthermore, levels of lipid peroxides in muscle and serum, and muscle edema in the EPC group, were significantly lower than in the NM group. Histological examinations supported these results. These findings suggest that limiting OFR generation by EPC-K1 in the early phase of reoxygenation is more potent than depletion of neutrophils in reducing reperfusion injury.

Topics: Animals; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Isometric Contraction; Leukocyte Count; Lipid Peroxidation; Male; Muscle, Skeletal; Neutropenia; Neutrophils; Random Allocation; Rats; Rats, Inbred Lew; Reperfusion Injury; Vitamin E

EPC-K1, a phosphate diester of alpha-tocopherol and ascorbic acid, is a new hydroxyl radical scavenger. We examined the effects of EPC-K1 according to differences in the timing of its administration. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, muscle injury was evaluated in 4 groups: the first group received a sham operation, the second group was treated with an intravenous injection of EPC-K1 prior to ischemia, the third group was treated with EPC-K1 prior to reperfusion, and the fourth group was controls. Compared with the control group, both the preischemic and pre-reperfusion EPC-K1-treated groups showed a statistically significant amelioration in the reduction of isometric muscle contraction. There were also significant reductions in the muscle and serum levels of thiobarbituric acid reactive substances (TBA-RS) and muscle damage, indicated by the biochemical and histological study. A comparison of the timing of EPC-K1 administration revealed that only the muscle TBA-RS level in the pre-reperfusion EPC-K1-treated group was significantly higher than that in the preischemic EPC-K1-treated group. These observations indicate that EPC-K1 not only by preischemic but also by pre-reperfusion administration acted effectively on reperfusion injury in muscle, thereby improving muscle function.

Topics: Animals; Antioxidants; Ascorbic Acid; Biopsy; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Free Radical Scavengers; Injections, Intravenous; Ischemia; Isometric Contraction; Male; Muscle, Skeletal; Random Allocation; Rats; Rats, Inbred Lew; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

1. The ability of EPC-K1 to improve myocardial infarction was evaluated in a rat model with coronary artery occlusion and reperfusion. 2. The myocardial infarct size was 30.5 +/- 1.7% by intravenous (i.v.) administration and 28.8 +/- 2.7% by intraduodenal (i.d.) administration of the saline EPC-K1 at doses between 1 and 10 mg/kg, i.v. and at doses between 50 and 200 mg/kg, i.d., reduced myocardial infarct size dose dependently. Significant reduction in myocardial infarct size was found at a dose of 10 mg/kg, i.v., and 200 mg/kg, i.d.

Topics: Animals; Antioxidants; Arterial Occlusive Diseases; Ascorbic Acid; Combined Modality Therapy; Coronary Disease; Disease Models, Animal; Free Radical Scavengers; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Vitamin E

L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl- 2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt (EPC-K1), a phosphate diester of alpha-tocopherol and ascorbic acid, is a potent antioxidant. We examined the effects of EPC-K1 on ischemia-reperfusion injury in the skeletal muscle of rats, using an ischemic revascularized hind limb model. Warm ischemia (25 degrees C), produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, skeletal muscle injury was evaluated in 2 groups: one group treated by intravenous injection of EPC-K1 (10 mg/kg) prior to ischemia, and a group of controls. The EPC-K1-treated group showed a statistically significant amelioration in the reduction of the isometric muscle contraction, inhibition of the elevation of the muscle wet- to dry-weight ratio, limitation of the muscle level of thiobarbituric acid reactive substances and the serum levels of creatine phosphokinase, lactate dehydrogenase and mitochondrial glutamic oxaloacetic transaminase, and reduction of the extent of muscle injury according to the histological findings. These observations indicate that EPC-K1 acted effectively on ischemia-reperfusion injury in the rat skeletal muscle and thereby improved muscle function.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Drug Evaluation, Preclinical; Free Radical Scavengers; Isometric Contraction; Male; Muscle, Skeletal; Rats; Rats, Inbred Lew; Reperfusion Injury; Vitamin E