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PubMed2003

[Advances in the diagnosis and treatment of cerebral ischemia during the acute phase].

Recent advances in MRI technology and the development of effective neuroprotective agents has improved the outcome of stroke. In order to salvage tissue after an ischemic insult it is important to differentiate the core and penumbra area of the ischemic lesion. The penumbra surrounds the ischemic core, damage in this area is reversible if effective neuroprotective agents are given and reperfusion occurs. In this symposium detection of penumbra in an ischemic lesion using diffusion weighted imaging (DWI) and perfusion imaging (PI), diffusion-perfusion mismatch, and indications for thrombolytic therapy are discussed. If a hypoperfusion area is revealed with PI without a corresponding lesion indicated with DWI or when the DWI lesion is less than one third of the PI lesion, combined thrombolytic and neuroprotective therapies are recommended. In contrast, when both PI and DWI show an identical lesion, only neuroprotective therapy is advised. Additionally, newly developed neuroprotective agents, especially the combined effect of rt-PA and the immunosuppressant, FK506, on an embolic infarct model are discussed.

Acute-Phase Reaction↗
PubMed2005

[A case of common carotid artery dissection showing remission in short-term].

We report a case of left common carotid artery dissection showing complete remission in the short term. A 48-year-old man presented a 1-week history of weakness in the right arm. Neurological findings revealed mild motor weakness of the right upper extremity. Magnetic resonance imaging (MRI) showed sporadic cerebral infarction and hemorrhagic infarction in the area of the left middle cerebral artery (MCA) and the posterior border zone. Computed tomographic angiography (CTA) revealed irregular stenosis with a smooth surface in the left common carotid artery and ultrasonography indicated an iso-echoic lesion in the same area. ECD-single-photon emission tomography (SPECT) showed low perfusion only in the infarcted territory. Conservative therapy using a free radical scavenger and aspirin was carried out and the patient displayed full neurological recovery. After a 3-week follow-up period, carotid angiography and CTA showed almost complete disappearance of the stenotic lesion.

Aortic Dissection↗
PubMedDate not supplied

MCI-186 inhibits tumor growth through suppression of EGFR phosphorylation and cell cycle arrest.

BACKGROUND: It has been suggested that radicals stimulate tumor cell growth. We examined if the hydroxyl radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), affects tumor growth in vitro. MATERIALS AND METHODS: Human hepatocarcinoma HepG2, mesothelioma MSTO-211H, gastric carcinoma TMK-1 and breast carcinoma MCF-7 were used for cell proliferation assay. Cell cycle analysis was performed using propidium iodide for fluorescence activated cell sorter. By Western blotting, EGF receptor (EGFR) phosphorylation and EGFR expression were analyzed. RESULTS: Growth inhibition was observed from 10 microM to 300 microM of MCI-186 in a dose-dependent manner. Cell cycle analysis revealed that MCI-186 arrested the cell cycle at the G0/G1-phase. MCI-186 inhibited EGF-stimulated cell growth. The phosphorylation level of EGFR was decreased by MCI-186, but the EGFR level was unchanged. CONCLUSION: From the data obtained, we suggest that tumor inhibition by MCI-186 was due, at least in part, to the modulation of EGFR signaling and cell cycle arrest.

Antineoplastic Agents↗
PubMedDate not supplied

Effects of a free radical scavenger, MCI-186, on ischemia-reperfusion injury during extended liver resection in dogs.

BACKGROUND/AIMS: In liver surgery, total clamping of the portal triad (Pringle's procedure) is commonly used, and this sometimes causes liver failure. This study evaluated the effects of a free radical scavenger, MCI-186, on ischemia-reperfusion injury during liver resection in dogs. METHODOLOGY: The experimental animals were divided into two groups. In the MCI group (n = 6), MCI-186 (6mg/kg/h) was administered twice, through a catheter placed in the right hepatic vein: the first time was from 0.5 hours before the onset of ischemia until ischemia by partial inflow occlusion, and the second was from 0.5-hours before reperfusion until reperfusion. In the control group (n = 6), vehicle (physiological saline) was administered in the same manner. RESULTS: The serum AST, ALT, and LDH levels were significantly (P < 0.05) lower in the MCI group than in the control group. Hepatic tissue blood flow 0.5 hours after reperfusion was significantly (P < 0.05) higher in the MCI group than in the control group. Histological tissue damage was mild, and tissue MDA levels were significantly (P < 0.05) lower in the MCI group than in the control group. CONCLUSIONS: MCI-186 ameliorates the ischemia-reperfusion injury caused by Pringle's procedure during extended liver resection.

Animals↗
PubMed2005

[Bilateral multiple border zone infarctions after massive bleeding: report of two cases].

We present two patients who developed bilateral border zone brain infarctions after massive bleeding. Patient 1 was a 46-year old woman who developed bilateral visual disturbance and left hand monoparesis after excessive menstruation with severe anemia. Diffusion-weighted MRI of brain showed multiple border zone infarcts bilaterally in cerebral and cerebellar hemispheres while brain MRA was normal. Patient 2 was a 67-year old man who developed disturbance of consciousness and right hemiplegia after upper gastrointestinal tract bleeding. Diffusion-weighted MRI of brain showed bilateral multiple border zone infarcts in cerebral hemispheres, although he had asymptomatic occlusion of the left internal carotid artery. The bilateral multiple border zone infarcts are one of the key findings suggesting the presence of anemic hypoxia as a result of global brain hypoperfusion caused by massive blood loss.

Aged↗
PubMedDate not supplied

Inhibition of antipyrine metabolite formation. Steady state studies with cimetidine and metyrapone in rats.

Antipyrine metabolite kinetics have been characterized in rats receiving an intravenous infusion of either saline, cimetidine, or metyrapone. 14CO2 exhalation rate-time profiles following [N-methyl-14C] antipyrine administration demonstrate that, when either cimetidine or metyrapone is maintained at a steady state plasma concentration, a constant degree of inhibition is evident. Under the conditions imposed in this in vivo study, the inhibitory potency of metyrapone is approximately 6 times that observed with cimetidine. Rate constants for the formation of 4-hydroxy-, 3-hydroxymethyl-, and norantipyrine have been calculated using breath and urinary metabolite data under the steady state inhibitory states. Metyrapone nonselectively inhibits the formation of all three oxidative metabolites by approximately one-third. Cimetidine inhibition is selective where rates of 3-methyl-hydroxylation and N-demethylation are reduced by 50% yet 4-hydroxylation is unaffected. The value of assessing inhibitory responses under steady state conditions is discussed and the nonlinear nature of the kinetics of inhibition, when a single bolus dose of inhibitor is used, is illustrated by means of computer simulation.

Animals↗
PubMed1982

Automated high-performance liqiud chromatographic method for the determination of antipyrine and its metabolites in urine. Some preliminary results obtained from smokers and non-smokers.

A simple, accurate and fully automated high-performance liquid-chromatographic method was developed for the simultaneous determination of antipyrine (AP), 3-hydroxymethylantipyrine (3HMA), 4-hydroxyantipyrine (4OHA) and norantipyrine (NORA) in urine. This method requires no extraction step and only one chromatographic run with the use of a reversed-phase system. The coefficient of variation (%) (n = 8 each) was: 4.14 for AP, 2.31 for 3HMA, 3.48 for 4OHA, and 2.71 for NORA. The method was applied to studies on AP metabolism in three smokers and three non-smokers who received an oral 10 mg/kg dose of AP. These preliminary results suggest that smokers appear to excrete more 4OHA and NORA in the urine than non-smokers.

Adult↗
PubMed1994

Effects of an antistroke agent MCl-186 on cerebral arachidonate cascade.

Activation of the cerebral arachidonate (AA) cascade is one of the major causes of edema and tissue injury in cerebral ischemia, particularly after reperfusion. The cascade produces toxic oxygen radicals responsible for peroxidative neurodegeneration and synthesizes, the potent edematous inducer, leukotrienes. The present study was undertaken to evaluate the effect of MCl-186 (3-methyl-1-phenyl-pyrazolin-5-one), a radical scavenger and antioxidant which has beneficial anti-ischemic actions, on the cerebral AA cascade. Postischemic treatment with MCl-186 (1.0 and 3.0 mg/kg i.v.) significantly inhibited the aggravation of cortical edema seen 60 min after recirculation following 30 min of ischemia in gerbils. An antilipoxygenase agent, FPL-55712 (7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2- hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid, monosodium salt; 10 mg/kg i.v.) or AA-861 ((2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinon e; 60 mg/kg i.p.) was also effective in this model; however, indomethacin (4 mg/kg i.p.), a cyclooxygenase inhibitor, was ineffective. Concomitant treatment with MCl-186 (0.1-3.0 mg/kg i.v.) remarkably inhibited the swelling observed 24 hr after cortical infusion of AA (80 micrograms) in rats. Similarly, antilipoxygenase agents clearly inhibited the AA-induced edema. Furthermore, postischemic treatment with MCl-186 (0.3-3.0 mg/kg i.v.) inhibited the facilitation of cerebral leukotriene synthesis seen 15 min after recirculation following 30 min of ischemia in gerbils. These findings suggest that the site of action of MCl-186 as an anti-ischemic agent may be closely associated with the cerebral AA cascade, especially the lipoxygenase system, activated by ischemia-reperfusion.

Animals↗
PubMed1994

Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions.

The anti-ischemic effects and a possible mechanism of a new antistroke agent, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186), were studied. Preischemic treatment with MCI-186 (3 mg/kg i.v.) facilitated the recovery of electrocorticographic activity and prolonged survival time in global complete ischemia of rats; MCI-186 (1 and 3 mg/kg i.v.) also mitigated dysfunction of the blood-brain barrier and energy failure in hemispheric embolization of rats. Postischemic treatment with MCI-186 (3 mg/kg i.v.) decreased cortical infarction in focal embolization of rats. MCI-186 (0.6-2.4 mM) inhibited the OH.-induced hydroxylation of salicylate (maximal inhibition, 40.2%), but at 100 microM it did not influence O2- generation. MCI-186 inhibited the formation of linoleic acid-conjugated dienes caused by OH. (IC50 = 32.0 microM). Also, concurrent administration of MCI-186 (3-100 mg/kg i.v.) ameliorated hyperglycemia, hyperlipopeoxidemia and degranulation of beta-cells in alloxan (40 mg/kg i.v.)-treated rats. In addition, MCI-186 inhibited iron-dependent peroxidation in rat brain homogenates and mitochondrial homogenates (IC50 = 15.0 and 2.3 microM, respectively) and prevented iron-dependent peroxidative disintegration of mitochondrial membranes (IC50 = 39.0 microM). These findings suggest that MCI-186 has potent anti-ischemic actions and that its mechanism may be closely associated with beneficial antioxidant activities.

Alloxan↗
PubMed1996

Identification of the human hepatic cytochromes P450 involved in the in vitro oxidation of antipyrine.

Antipyrine biotransformation has been used extensively in clinical studies as a marker for general hepatic oxidative or cytochrome P450 (P450)-mediated, metabolism. Studies have indicated that more than one P450 is involved in the formation of the three major human metabolites, 4-hydroxyantipyrine, norantipyrine, and 3-hydroxymethylantipyrine. However, the specific P450s involved have not yet been determined. We have developed a sensitive method for the measurement of antipyrine metabolites formed in the in vitro incubations and applied it to determine the P450s participating in the formation of each metabolite in human liver microsomes. The identification of these P450s was accomplished through the use of simple and multivariate regression analysis, selective chemical inhibitors, and microsomes containing cDNA-expressed enzymes. These methods implicated P450s 1A2, 3A, and 2A6 in the formation of 4-hydroxyantipyrine. The predominant form involved in 3-hydroxymethylantipyrine formation was found to be 1A2, although 2C9 and 2E1 seemed to participate to a lesser extent. All forms considered (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A) seemed to be involved in the formation of norantipyrine, although 1A2 and 2C9 only were accepted in multivariate regression analysis. Thus, antipyrine clearance is indeed a general measure of P450 oxidative capacity, with a slight to moderate weight toward 1A2, depending on the degree of 1A2 expression. Because of the multiplicity of the enzymes involved in the formation of each metabolite, the determination of these individual metabolites would be ineffective as an indicator of the levels of specific P450 forms in human subjects.

Antipyrine↗
PubMed1997

Effects of a novel free radical scavenger, MCl-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model.

We investigated the effects of a free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCl-186), on infarct areas, neurological deficits and regional cerebral blood flow (rCBF), with use of a rat thrombotic distal middle cerebral artery (dMCA) occlusion model to elucidate its possible therapeutic effects on focal cerebral ischemia. In addition, we have attempted to measure 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB), which is the major oxidation product of MCl-186, in the penumbral cortex of a thrombotic dMCA occlusion model. Postischemic treatment with MCl-186 (3 mg/kg) significantly (P < .05) decreased the size of the cerebral infarcts 1 day after dMCA occlusion. MCl-186 (3 mg/kg) significantly (P < .05) improved the neurological deficits 1 day after dMCA occlusion. On the contrary, MCl-186 had no effect on rCBF 1 day after dMCA occlusion. MCl-186 mainly reacted into OPB by peroxidation in rat brain homogenates. Furthermore, the increase in OPB content in the ischemic penumbral cortex tissue was confirmed after 90 min of MCl-186 perfusion. These results suggest that MCI-186 has a protective effect on brain ischemia by reacting with oxygen radicals and that oxygen radicals are closely related to postischemic brain injury.

Animals↗
PubMed1997

[In vitro evaluation of metabolic change in forebrain ischemia model of rat using proton magnetic resonance spectroscopy].

Metabolic disruption resulted from cerebral ischemia and post-ischemia reperfusion injury was studied using proton magnetic resonance spectroscopy (1H MRS). We also analyzed the effect of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) which can scavenge free radicals induced in the brain tissue due to ischemic-reperfusion in this experiment. The ischemic model was produced using rat forebrain ischemic model (Pulsinelli's 4 vessels occlusion model). Post-ischemic reperfusion was also induced by the re-opening of the occluded common carotid arteries. The occluded time was 30 min and reperfusion time 0, 10, 30, 60 min. We obtained the specimens in the cortex under microwave fixation. Choline and acetate increased during ischemia and gradually decreased during reperfusion period. These two signals seen in 1H MRS are supposed to represent cell membrane components (products) and the increase of these signals after reperfusion seems to be related to the post ischemic reperfusion injury due to the explosive increase of free radicals. Lactate, which is induced by anaerobic glycolysis, increased during ischemia and promptly disappeared after reperfusion. The treatment of pre-ischemic administration of MCI-186 significantly suppressed increases of choline and acetate. As far as lactate is concerned, post-ischemic administration of this drug significantly reduced its increase at the point of reperfusion. Our results suggest that MCI-186 alternates changes induced by ischemic-reperfusion injury in membranous metabolism, probably due to its free radical scavenging action.

Acetates↗