Effect of Cloricromene During Ischemia and Reperfusion of Rabbit Hindlimb: Evidence for an Involvement of Leukocytes in Reperfusion-Mediated Tissue and Vascular Injury

Cirillo, R; Salvatico, Estela; Aliev, Gjumrakch; Prosdocimi, Marco

doi:10.1097/00005344-199212000-00018

Cited by 23 publications

(14 citation statements)

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“…There is a decline in polyunsaturated fatty acids (PUFA) (Prasad et al, 1998;Lin et al, 2001) and substantially increased levels of lipid peroxidation markers (Smith et al, 1996a;Lin et al, 2001), protein oxidation and modification (Markesbery, 1997;Markesbery and Carney, 1999), DNA oxidation (Mecocci et al, 1993; and RNA oxidation (Nunomura et al, 1999a,b;Aliev et al, 2002c;Shi et al, 2002b) during AD. In addition, oxidative stress markers such as advanced glycation end products (AGE) and lipid peroxidation adducts, or other oxidative stress markers are detectable in both NFT and SP are increased in AD (Markesbery, 1997;Smith et al, 1994;1996a,b;Sayre et al, 1997;Markesbery and Carney, 1999;Perry et al, 2000), and in postischemic (Granger et al, 1989;Cirillo et al, 1992;Salvatico et al, 1994;Sala et al, 1996), atherosclerotic 2000a,c;2001b), and tumor tissues (Shankar et al, 1998;Aliev et al, 2002d).…”

Section: Vascular Lesions As a Primary Target And Initiator Of Oxidatmentioning

confidence: 99%

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

et al. 2003

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Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.

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Section: Vascular Lesions As a Primary Target And Initiator Of Oxidatmentioning

confidence: 99%

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

et al. 2003

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“…The mechanisms through which cloricromene elicits this beneficial activity and indeed that responsible for protection in other models of myocardial ischaemia (Milei et al, 1992;, peripheral ischaemia (Cirillo et al, 1992) or shock (Sturniolo et al, 1989;Squadrito et al, 1992) have essentially remained unknown. However, while cloricromene at 30 and 300 fg kg-' min-' significantly reduced infarct size, the determination of platelet and MPO activity in this study clearly supports inhibition of leukocyte infiltration as the primary mode of action of cloricromene.…”

Section: Discussionmentioning

confidence: 99%

“…Pathophysiologically, cloricromene has protective activity in rat models of shock caused by splanchnic artery occlusion (Sturniolo et al, 1989), haemorrhage (Sturniolo et al, 1991), endotoxin (Squadrito et al, 1992) or peripheral ischaemia in the rabbit hindlimb (Cirillo et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Lidbury

Cirillo

Vane

1993

British J Pharmacology

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1 Cloricromene is a non-anticoagulant coumarin derivative with anti-platelet and anti-leukocyte properties, which has beneficial effects in various models of ischaemia and shock. 2 We have assessed the effects of cloricromene on (a) ex vivo platelet aggregation, and (b) infarct size using a model of myocardial ischaemia in the anaesthetized rabbit.3 Cloricromene (1-1000 tgkg' min'I for 15min) induced a dose-dependent inhibition of ex vivo platelet aggregation, causing only a minimal increase in heart rate and no change in mean arterial blood pressure. The inhibitory activity was considerably stronger when platelet aggregation was induced by collagen than by ADP. 4 Cloricromene inhibited ex vivo platelet aggregation in rabbits pretreated with indomethacin (5 mg kg-') and this inhibition persisted for 30-60 min.5 The model of myocardial ischaemia involved 1 h occlusion of the first antero-lateral branch of the left coronary artery followed by 2 h of reperfusion. Infusion of cloricromene (30 or 300 gg kg-' min-'), ibuprofen (80 iLg kg-' min') or vehicle began 15 min prior to occlusion, and continued throughout the experiment.6 While area at risk was similar for all groups studied, cloricromene (30 or 300 ftg kg' min-') or ibuprofen caused a reduction in infarct size, and decreased myeloperoxidase activity in the tissue of the infarcted myocardium.7 Cloricromene at 300 pg kg-' min-' also reduced the occlusion-induced elevation of the ST-segment of the rabbit electrocardiogram, and inhibited platelet aggregation ex vivo. Ibuprofen or cloricromene at 30 fg kg-' min'-had no effect on either the ST-elevation or platelet reactivity.8 Thus, cloricromene exhibits a cardioprotective activity via an inhibition of leukocyte infiltration, in the presence (300 tLg kg-l min-') or absence (30 ltg kg'-min-') of inhibition of platelet activity ex vivo.The anti-aggregatory activity of cloricromene acts via a mechanism that is either different from, or in addition to, inhibition of cyclo-oxygenase, and is of long duration.

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“…1 15). Lack of statistical significance in ANLV can be accounted for by the inherent variability of the left ventricular mass as opposed to the size of the LAD perfused bed.…”

Section: Myocardial Infarct Sizementioning

confidence: 99%

Cloricromene Reduces Infarct Size and Alters Postischaemic Blood Flow Defects in Dog Myocardium

Groban

Zvara

Deal

et al. 1998

Clin Exp Pharma Physio

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1. The aim of the present investigation was to evaluate the effect of cloricromene on myocardial infarct size, regional myocardial blood flow and neutrophil accumulation in a canine model of ischaemia-reperfusion. 2. Dogs were instrumented to measure blood pressure, left anterior descending (LAD) coronary flow (flow probe) and regional myocardial blood flow (coloured microspheres). Two groups were studied: (i) CLO (n = 8) received an infusion of cloricromene (15 micrograms/kg per min); and (ii) VEH (n = 8) received saline. Infusions began at the onset of ischaemia (60 min) and continued through reperfusion (180 min). 3. Haemodynamic responses were not different between groups. Cloricromene reduced the area of necrosis expressed as a percentage of the area at risk from 35 +/- 3% in the VEH group to 23 +/- 4% in the CLO group (P < 0.05). Regional myocardial blood flow in the ischaemic region was different between groups; VEH dogs showed an early reperfusion hyperaemia followed by a progressive reduction in flow, while CLO dogs exhibited a gradual increase in reflow in the absence of an early hyperaemic response (P < 0.05). Left anterior descending flow was enhanced during the reperfusion period in the CLO group compared with VEH (P < 0.05). Cloricromene reduced polymorphonuclear neutrophil (PMN) infiltration (myeloperuxidase activity) in all myocardial regions when compared with VEH (non-ischaemic zone, 0.34 +/- 0.54 vs 0.05 +/- 0.01 IU/100 mg; ischaemic zone, 2.03 +/- 0.80 vs 0.24 +/- 0.08 IU/100 mg; and necrotic zone, 0.56 +/- 0.04 vs 3.59 +/- 1.09 IU/100 mg for VEH vs CLO groups, respectively; P < 0.01). In a separate in vitro preparation, cloricromene reduced adherence of platelet-activating factor (PAF)-stimulated PMN to canine coronary endothelium. Stimulation of PMN by 100 nmol/L PAF resulted in adherence of 176 +/- 36 compared with 48 +/- 12 cells/mm2 in PAF-stimulated PMN treated with 100 mumol cloricromene (P < 0.001). 4. These data indicate that cloricromene reduces myocardial infarct size in a canine model of ischaemia-reperfusion injury. Postischaemic blood flow patterns are significantly different in cloricromene-treated dogs. Cloricromene-mediated reductions in infarct size, neutrophil accumulation and adherence may play a role in this effect.

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Effect of Cloricromene During Ischemia and Reperfusion of Rabbit Hindlimb: Evidence for an Involvement of Leukocytes in Reperfusion-Mediated Tissue and Vascular Injury

Cited by 23 publications

References 0 publications

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

Dissociation of the anti‐ischaemic effects of cloricromene from its anti‐platelet activity

Cloricromene Reduces Infarct Size and Alters Postischaemic Blood Flow Defects in Dog Myocardium

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