Effects of Sulfaphenazole Derivatives on Cardiac Ischemia–Reperfusion Injury: Association of Cytochrome P450 Activity and Infarct Size

Ishihara, Yasuhiro; Sekine, Masaya; Hamaguchi, Ai; Kobayashi, Yusuke; Harayama, Takashi; Nakazawa, Makoto; Shimamoto, Norio

doi:10.1254/jphs.10103fp

Cited by 14 publications

(11 citation statements)

References 30 publications

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“…SPZ can directly scavenge ROS 16) and suppress ROS production from the CYP2C family, 17) thus indicating that the SPZ-induced reduction of ischemia-reperfusion injury arises from both the ROS scavenging and CYP inhibition abilities of SPZ. 12,13,16) The present results show that systemic SPZ treatment after ICH induction by COL helps to prevent neurological deficits, striatal dysfunction, brain edema and lipid peroxidation in rats.…”

supporting

confidence: 54%

“…11) ROS produced by CYPs induce oxidative stress which causes various pathological conditions. [11][12][13] Some CYP family proteins, especially the CYP2C subfamily, are expressed in not only brain regions such as the cortex, hippocampus and basal ganglia, 14) but also in vascular endothelial cells, 15) thus suggesting the possibility that ROS derived from CYP result in numerous cerebral vascular disorders.…”

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confidence: 99%

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Effects of Sulfaphenazole after Collagenase-Induced Experimental Intracerebral Hemorrhage in Rats

Hama

Ishihara

Watanabe

et al. 2012

Biological & Pharmaceutical Bulletin

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Treatment of intracerebral hemorrhage is often pointless, although considerable effort has been devoted to developing treatments for ischemic stroke. The purpose of this study was to determine the influence of drugs in improving neurological outcomes with pharmaceutical therapy after intracerebral hemorrhage. The free-radical hypothesis for intracerebral hemorrhage is based on the cytotoxicity triggered by blood components and its degradation products, such as heme and iron as a potent pro-oxidant atom. Sulfaphenazole (SPZ) has a different mechanism such as reactive oxygen species scavenging, in addition to the inhibition of superoxide production by cytochrome P450. The present study investigated the properties of SPZ in collagenase-induced intracerebral hemorrhage rat brain damage. The results show that systemic SPZ treatment after intracerebral hemorrhage reduces striatal dysfunction, the elevation of lipid peroxidation, and brain edema in the rat. These results suggest that SPZ is a potentially effective therapeutic approach for intracerebral hemorrhage as the effect of SPZ was initiated for either 1 h or 3 d post-intracerebral hemorrhage.Key words intracerebral hemorrhage; magnetic resonance imaging; striatum; brain edema; rotation behavior; sulfaphenazole Intracerebral hemorrhage (ICH) results from the rupture of a blood vessel in the brain, and is a major public health problem, because ICH leads to a high rate of death and disability in adults. The 30-d mortality rate is approximately 50%, and most survivors (more than 80%) are left with neurological disabilities.1) Primary ICH accounts for approximately 25% of all strokes in Asian populations including the Japanese, 2) and spontaneous ICH represents one of the most devastating types of stroke.The pathophysiology of ICH is caused by a complex chain of events starting with disruption of the blood-brain barrier (BBB) and infiltration of blood components into the brain parenchyma, resulting in a progressive edema, which starts in the first 24 h and remains elevated over several days.3) The development of therapies relies on the use of animal models. 4)The animal models are commonly produced by manipulation in the striatum, because that is the most common site of ICH (more than 50% of all ICH).1) Rosenberg and coworkers have developed a particularly elegant rat model in which intrastriatal injection of bacterial collagenase (COL) disrupts the basal lamina of cerebral capillaries and causes bleeding into the brain tissue. 5) A highly reproducible brain injury due to ICH and the ability to follow changes in vivo are necessary to properly evaluate treatments.Oxidative stress is thought to be deeply involved in secondary brain injury after ICH.6) The amount of oxidative DNA is increased after ICH in the animal model, and administration of a free radical scavenger, edaravone suppressed DNA oxidation and brain damage after ICH.7) Iron plays a role in a proposed mechanism for the generation of oxidative stress after ICH.8) Iron ions are generated by hemoglobin breakd...

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confidence: 54%

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confidence: 99%

Effects of Sulfaphenazole after Collagenase-Induced Experimental Intracerebral Hemorrhage in Rats

Hama

Ishihara

Watanabe

et al. 2012

Biological & Pharmaceutical Bulletin

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“…SPZ is a potent cytochrome P450 inhibitor (30). We previously reported that SPZ suppressed cardiac reperfusion injury by inhibiting ROS production from cytochrome P450 (11,12). We showed that BimEL expression was elevated by ROS stimuli (31).…”

Section: Discussionmentioning

confidence: 77%

“…We previously reported that intravenous administration of SPZ at the time of reperfusion reduced the myocardial infarct size and improved the cardiac function in a rat model of I/R (11). We further revealed that the suppressive effects of SPZ on myocardial infarction were brought about by the attenuation of the cardiac ROS levels derived from cytochrome P450 (12).…”

Section: Introductionmentioning

confidence: 87%

Sulfaphenazole Attenuates Myocardial Cell Apoptosis Accompanied With Cardiac Ischemia^|^ndash;Reperfusion by Suppressing the Expression of BimEL and Noxa

Ishihara

Shimamoto

2012

J Pharmacol Sci

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Abstract. We previously reported the administration of a potent cytochrome P450 inhibitor, sulfaphenazole (SPZ), to suppress oxidative stress and the extension of myocardial infarct size in a rat model of cardiac ischemia-reperfusion (I/R). The aim of this study was to investigate the effects of SPZ on the myocardial cell apoptosis induced by I/R in rats. I/R injury was evoked by ligation of the left anterior descending coronary artery for 1 h, followed by reperfusion for 3 h. TUNEL-positive nuclei were detected and nucleosomal DNA fragmentation was observed 3 h after reperfusion. The administration of SPZ largely suppressed the cardiac DNA fragmentation induced by I/R. A pan-caspase inhibitor, z-VAD-fmk, had no effect on DNA fragmentation. Caspase-3/7 was not activated 3 h after reperfusion. Decreases in the mitochondrial membrane potential and cytochrome c release from the mitochondria to cytosol were detected 3 h after reperfusion. The expression levels of BimEL and Noxa were elevated 3 h after reperfusion. These phenomena were suppressed by the administration of SPZ. Taken together, treatment with SPZ could attenuate the myocardial cell apoptosis accompanied with I/R by inhibiting the mitochondrial dysfunction due to decreases in the expression of BimEL and Noxa.

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“…Numerous potential ROS sources, such as NADPH oxidase, xanthine oxidase, cyclooxygenase, lipoxygenase, nitric oxide synthases, the mitochondrial respiratory chain, and P450 enzymes, have been reported in cardiac I/R studies (Ishihara et al, 2010).…”

Section: Cp Reduces Miri Via Increasing Eet Levels In Rats 885mentioning

confidence: 99%

Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats

Hao

Jiang

et al. 2016

Drug Metabolism and Disposition

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Accumulating data suggest that epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid, both cytochrome P450 (P450) enzyme metabolites of arachidonic acid (AA), play important roles in cardiovascular diseases. For many years, the cardiotonic pill (CP), an herbal preparation derived from Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum, has been widely used in China for the treatment of coronary artery disease. However, its pharmacological mechanism has not been well elucidated. The purpose of this study was to investigate the chronic effects of the CP on myocardial ischemia-reperfusion injury (MIRI) and AA P450 enzyme metabolism in rats (in vivo) and H9c2 cells (in vitro). The results showed that CP dose dependently (10, 20, and 40 mg/kg/d; 7 days) mitigated MIRI in rats. The plasma concentrations of EETs in CP-treated ischemia-reperfusion (I/R) rats (40 mg/kg/d; 7 days) were significantly higher (P < 0.05) than those in controls. Cardiac Cyp1b1, Cyp2b1, Cyp2e1, Cyp2j3, and Cyp4f6 were significantly induced (P < 0.05); CYP2J and CYP2C11 proteins were upregulated (P < 0.05); and AA-epoxygenases activity was significantly increased (P < 0.05) after CP (40 mg/kg/d; 7 days) administration in rats. In H9c2 cells, the CP also increased (P < 0.05) the EET concentrations and showed protection in hypoxia-reoxygenation (H/R) cells. However, an antagonist of EETs, 14,15-epoxyeicosa-5(Z)-enoic acid, displayed a dose-dependent depression of the CP's protective effects in H/R cells. In conclusion, upregulation of cardiac epoxygenases after multiple doses of the CP-leading to elevated concentrations of cardioprotective EETs after myocardial I/R-may be the underlying mechanism, at least in part, for the CP's cardioprotective effect in rats.

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Effects of Sulfaphenazole Derivatives on Cardiac Ischemia–Reperfusion Injury: Association of Cytochrome P450 Activity and Infarct Size

Cited by 14 publications

References 30 publications

Effects of Sulfaphenazole after Collagenase-Induced Experimental Intracerebral Hemorrhage in Rats

Effects of Sulfaphenazole after Collagenase-Induced Experimental Intracerebral Hemorrhage in Rats

Sulfaphenazole Attenuates Myocardial Cell Apoptosis Accompanied With Cardiac Ischemia^|^ndash;Reperfusion by Suppressing the Expression of BimEL and Noxa

Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats

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