Terutroban, a Thromboxane/Prostaglandin Endoperoxide Receptor Antagonist, Increases Survival in Stroke-Prone Rats by Preventing Systemic Inflammation and Endothelial Dysfunction: Comparison with Aspirin and Rosuvastatin

Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Milan, Italy.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2010; 334(1):199-205. DOI: 10.1124/jpet.110.165787
Source: PubMed


This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Salt-loaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B(2) levels, terutroban significantly increased survival (p < 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p < 0.001), and a delayed increase of proteinuria (p < 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1beta, transforming growth factor-beta, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.

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Available from: Anita Gianella, Apr 02, 2015
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    • "Thromboxane A 2 and isoprostanes can stimulate endothelial TP receptors and increase the expression of proinflammatory markers such as ICAM-1 and VCAM-1 [6]. In animal models, antagonism of the TP receptor preserves endothelium-dependent relaxation of isolated vessels [11], and clinical trials have shown improved endothelial function in patients with coronary artery disease by addition of the TP receptor antagonist terutroban to aspirin [12]. Whereas the vasoconstrictive effect of TP receptor signaling is well established [13] [14], only few studies have addressed the direct effects of thromboxane mimetics on human vascular SMCs. "
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    ABSTRACT: The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-Keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.
    Full-text · Article · Oct 2013 · Biochemical and Biophysical Research Communications
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    • "Terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, decreased cerebral mRNA expressions of IL-1β, transforming growth factor-β, and MCP-1 and increased survival in SHRSP [116]. These effects were similar to rosuvastatin and aspirin [116]. The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study was started in February 2006 [117]. "
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    ABSTRACT: Stroke is an important issue in public health due to its high rates both of morbidity and mortality, and high rate of disability. Hypertension, cardiovascular disease, arterial fibrillation, diabetes mellitus, smoking, and alcohol abuse are all risk factors for stroke. Clinical observations suggest that inflammation is also a direct risk factor for stroke. Patients with stroke have high levels of inflammatory cytokines in plasma, and immune cells, such as macrophages and T-lymphocytes, are noted within stroke lesions. These inflammatory events are considered as a result of stroke. However, recent studies show that plasma levels of inflammatory cytokines or soluble adhesion molecules are high in patients without stroke, and anti-inflammatory therapy is effective at reducing stroke incidence in not only animal models, but in humans as well. Statins have been shown to decrease the stroke incidence via anti-inflammatory effects that are both dependent and independent of their cholesterol-lowering effects. These reports suggest that inflammation might directly affect the onset of stroke. Microglial cells and blood-derived monocytes/macrophages play important roles in inflammation in both onset and aggravation of stroke lesions. We review the recent findings regarding the role of monocytes/macrophages in stroke.
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    • "Finally, occlusions of vessels (Figures 4D and 7D) develop as a reaction to microbleeds and can therefore be observed in infarct regions together with fresh and old microbleeds. We emphasize that in contrast to other authors, we did not apply a diet with 1% salt in drinking water (Lee et al, 2007; Gelosa et al, 2010). Therefore, in animals fed a salt-loaded diet, tissue infarctions occur in 80% of 30-week-old male SHRSP (Yamori and Horie, 1977; Tagami et al, 1987). "
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    ABSTRACT: Cerebral small vessel disease (CSVD) is associated with vessel wall changes, microbleeds, blood-brain barrier (BBB) disturbances, and reduced cerebral blood flow (CBF). As spontaneously hypertensive stroke-prone rats (SHRSP) may be a valid model of some aspects of human CSVD, we aimed to identify whether those changes occur in definite temporal stages and whether there is an initial phenomenon beyond those common vascular alterations. Groups of 51 SHRSP were examined simultaneously by histologic (Hematoxylin-Eosin, IgG-Immunohistochemistry, vessel diameter measurement) and imaging methods (Magnetic Resonance Imaging, 201-Thallium-Diethyldithiocarbamate/99m-Technetium-HMPAO Single Photon Emission Computed Tomography conducted as pilot study) at different stages of age. Vascular pathology in SHRSP proceeds in definite stages, whereas an age-dependent accumulation of erythrocytes in capillaries and arterioles represents the homogeneous initial step of the disease. Erythrocyte accumulations are followed by BBB disturbances and microbleeds, both also increasing with age. Microthromboses, tissue infarctions with CBF reduction, and disturbed potassium uptake represent the final stage of vascular pathology in SHRSP. Erythrocyte accumulations--we parsimoniously interpreted as stases--without cerebral tissue damage represent the first step of vascular pathology in SHRSP. If that initial phenomenon could be identified in patients, these erythrocyte accumulations might be a promising target for implementing prophylactic and therapeutic strategies in human CSVD.
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