ticagrelor and Disease-Models--Animal

Thrombotic cardio-cerebrovascular diseases seriously threaten human health. Currently, conventional thrombolytic treatments are challenged by the low utilization, inferior thrombus penetration, and high off-target bleeding risks of most thrombolytic drugs, resulting in unsatisfactory treatment outcomes. Herein, it is proposed that these challenges can be overcome by precisely integrating the conventional thrombolytic strategy with photothermal therapy. After co-assembly engineering optimization, a fibrin-targeting peptide-decorated nanoassembly of DiR (a photothermal probe) and ticagrelor (TGL, an antiplatelet drug) is prepared for thrombus-homing delivery, abbreviated as FT-DT NPs. The elaborately engineered nanoassembly shows multiple advantages, including simple preparation with high drug co-loading capacity, synchronous delivery of two drugs with long systemic circulation, thrombus-targeted accumulation with self-indicating function, as well as photothermal-potentiated thrombus penetration and thrombolysis with high therapeutic efficacy. As expected, FT-DT NPs not only show bright fluorescence signals in the embolized vessels, but also perform photothermal/antiplatelet synergistic thrombolysis in vivo. This study offers a simple and versatile co-delivery nanoplatform for imaging-guided photothermal/antiplatelet dual-modality thrombolysis.

Topics: Animals; Disease Models, Animal; Drug Delivery Systems; Fibrinolytic Agents; Mice; Nanoparticles; Photothermal Therapy; Platelet Aggregation Inhibitors; Rats; Thrombolytic Therapy; Thrombosis; Ticagrelor

Ticagrelor is the first reversibly binding oral P2Y

Topics: Acute Coronary Syndrome; Animals; CARD Signaling Adaptor Proteins; Chlorides; Disease Models, Animal; Humans; Inflammasomes; Inflammation; Macrophages; Mice, Inbred C57BL; Models, Biological; NLR Family, Pyrin Domain-Containing 3 Protein; Protein Multimerization; Receptors, Purinergic P2Y12; Signal Transduction; Ticagrelor

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a sodium-glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin and ticagrelor have additive effects in attenuating the progression of diabetic cardiomyopathy in T2DM mice.. Eight-week-old BTBR and wild-type mice received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or their combination for 12 weeks. Heart function was evaluated by echocardiography and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and immunoblotting.. Both drugs attenuated the progression of diabetic cardiomyopathy as evident by improvements in left ventricular end-systolic and end-diastolic volumes and left ventricular ejection fraction, which were further improved by the combination. Both drugs attenuated the activation of the NOD-like receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was significantly greater than each drug alone on myocardial tissue necrotic factorα (TNFα) and interleukin-6 (IL-6) levels, suggesting additive effects. The combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA levels than each drug alone. While both drugs activated adenosine mono-phosphate kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were significantly greater than those of ticagrelor.. Both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, the activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR mice.

Topics: AMP-Activated Protein Kinases; Animals; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Disease Progression; Enzyme Activation; Fibrosis; Glucosides; Inflammasomes; Male; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred C57BL; Myocytes, Cardiac; NLR Family, Pyrin Domain-Containing 3 Protein; Purinergic P2Y Receptor Antagonists; Signal Transduction; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ticagrelor; TOR Serine-Threonine Kinases; Ventricular Function, Left; Ventricular Remodeling

Bypass graft surgery remains to be an important treatment option for left main and multivessel coronary artery disease. Approximately 2% of saphenous vein grafts are lost immediately after the coronary artery bypass graft operations and 12% in the first month due to thrombosis.. To administer one anticoagulant and two antiplatelet agents in a way that locally affects the vein graft before the bypass operation and to thereby analyse their effects on early graft thrombosis.. Animal experimentation.. Since ticagrelor was used locally for the first time in this study, its efficacy in combination with other drugs (acetylsalicylic acid, acetylsalicylic acid and ticagrelor, and acetylsalicylic acid + ticagrelor + unfractionated heparin) was examined on rats including control (untreated) and sham (pluronic gel) group (n=14 for each group). Before the tunica adventitia layer of the femoral veins was bypassed to the femoral artery, it was coated with the drug-eluting pluronic F-127 gel. The presence or absence of thrombus in the vein graft samples was recorded under light microscopy. In vein graft preparations where thrombus was detected, the thrombus area (μm. Locally effective acetylsalicylic acid-ticagrelor-unfractionated heparin complex has been shown to significantly reduce thrombus formation in vein grafts in this experimental model. Local administration of these drugs, which are routinely administered orally just before stent implantations, on the vein graft before the bypass is performed can prevent the loss of vein grafts due to thrombus, thereby reducing the mortality and morbidity of these patients.

Topics: Animals; Anticoagulants; Aspirin; Coronary Artery Bypass; Disease Models, Animal; Graft Enhancement, Immunologic; Heparin; Pathology; Platelet Aggregation Inhibitors; Poloxamer; Rats; Thrombosis; Ticagrelor; Veins

To evaluate the side effects of two antiplatelet agents - ticagrelor and eptifibatide - in mice with experimentally-induced inflammatory bowel disease.. This study was designed as a controlled, animal, drug safety investigation. C57Bl/6 mice were used to establish the ulcerative colitis model by exposure to dextran sulfate sodium (DSS), and divided into three experimental groups: eptifibatide-treated (150 µg/day intraperitoneally; n = 10), ticagrelol-treated (1 mg/day via gastric tube; n = 10), and DSS-control (plain drinking water; n = 10). An unmodeled non-DSS group served as the experimental control. Complete blood count was taken for all mice at baseline (day 0, treatment initiation) and after four days of treatment. On day 4, all animals were sacrificed for autopsy. The primary outcome measure was bleeding, and the secondary outcomes were change in platelet count, hemoglobin level, and hematocrit level.. Neither ticagrelor nor eptifibatide treatment produced a significant effect on DSS colitis mice for the safety parameters measured. Platelet count and hemoglobin and hematocrit levels were statistically similar between the three DSS groups and the non-DSS control group (P > 0.05). Autopsy found no evidence of recent bleeding in liver, spleen, central nervous system or serous cavities.. The antiplatelet agents ticagrelor and eptifibatide were safe in DSS colitis mice, suggesting their potential in humans suffering from ulcerative colitis, and supporting future safety studies.

Topics: Animals; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Eptifibatide; Hematocrit; Hemoglobins; Mice; Mice, Inbred C57BL; Platelet Aggregation Inhibitors; Platelet Count; Ticagrelor

Naoxintong Capsule (NXT), a Chinese medicine, has been widely used for the treatment of coronary heart disease (CHD) in clinics.. This study evaluated the cardioprotective effects of NXT alone and in combination with ticagrelor (TIC) and atorvastatin (ATO).. Qi deficiency and blood stasis rats were established by 8 weeks high fat diet feeding and 16 days exhaustive swimming and randomly divided into seven groups, that is, NXT (250, 500 and 1000 mg/kg/d), TIC (20 mg/kg/d), ATO (8 mg/kg/d), NXT (500 mg/kg/d)+TIC (20 mg/kg/d) and NXT (500 mg/kg/d)+ATO (8 mg/kg/d) group, with oral administration for 12 weeks. The contents of TC, TG, LDL-C, HDL-C, IL-1β, IL-6, IL-8, TNF-α, AST, ALT, SOD, MDA, CK-MB, LDH, TXA2, PGI2, IgA, IgG, IgM and C3 in serum were measured.. NXT + TIC group was significantly superior to the TIC group in decreasing the levels of TC (4.34 vs. 5.54), TG (3.37 vs. 4.66), LDL-C (1.21 vs. 1.35), LDH (4919.71vs. 5367.19) and elevating SOD level (248.54 vs. 192.04). NXT + ATO group was significantly superior to the ATO group in decreasing the levels of AST (195.931 vs. 241.63), ALT (71.26 vs. 83.16), LDH (4690.05 vs. 5285.82), TXA2 (133.73 vs. 158.67), IgG (8.08 vs. 9.80), C3 (2.03 vs. 2.35) and elevating the levels of HDL-C (1.19 vs. 0.91), SOD (241.91vs. 209.49).. The present findings demonstrate that the combined use of NXT with TIC and ATO had better integrated regulating effects than TIC and ATO, respectively. The mechanism of action requires further research.

Topics: Animals; Atorvastatin; Cardiotonic Agents; Coronary Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drugs, Chinese Herbal; Male; Qi; Rats; Rats, Sprague-Dawley; Ticagrelor

The purpose of this study was to determine whether ticagrelor, a classic anti-platelet drug, has a therapeutic effect on sepsis-induced myocardial injury.. The C57BL6J mice received oral ticagrelor (10, 25 and 50 mg/kg) for seven days after which cecum ligation and puncture (CLP) were performed. An adenosine-receptor antagonist (CGS15943) was administered two hours before CLP. After 24 h, cardiac function was measured using cardiac echocardiography, then the heart and blood were collected. Hematoxylin and eosin (HE) staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL staining) were used to observe pathological changes and cardiomyocyte apoptosis. Plasma concentration of TNF-α, IL-6 and adenosine and myocardial tissue levels of TNF-α and IL-6 were determined. Survival analysis was performed. Western blot was used to determine the expression of a signalling protein in the myocardial tissue.. The HE and TUNEL staining showed less inflammatory cell infiltration and less cardiomyocyte apoptosis in the ticagrelor group. Cardiac echocardiography showed preserved heart function in the ticagrelor group. Plasma TNF-α, IL-6 and relative expression of TNF-α and IL-6 in myocardial tissue were significantly lower in the ticagrelor group. Plasma adenosine levels were significantly higher in the ticagrelor group. Adenosine-receptor antagonists significantly blocked the protective effect of ticagrelor. Ticagrelor reduced the mortality of sepsis mice, and this reduction was blocked by the adenosine-receptor antagonist. Western blot showed that ticagrelor activated the phosphorylation of AKT and mTOR. Adenosine-receptor antagonists inhibited the activation of AKT and mTOR.. The protective effect of ticagrelor was dependent on adenosine-receptor activation, with downstream upregulation of phosphorylation of AKT and mTOR.

Topics: Adenosine; Animals; Apoptosis; Disease Models, Animal; Mice; Sepsis; Ticagrelor

This study was conducted to reveal the possible protective effects of ticagrelor and enoxaparin pretreatment against ischemia-reperfusion (IR)-induced injury on the lung tissue of a rat model.. Wistar albino rats were randomly divided into 4 groups as follows: group-1 (control-sham), group-2 (control-saline+IR), group-3 (ticagrelor+IR), group-4 (enoxaparin+IR). Before the ischemic period, saline, ticagrelor, and enoxaparin were administered to the 2nd-4th groups, respectively. In these groups, IR injury was induced by clamping the aorta infrarenally for 2 h, followed by 4 h of reperfusion except group-1. After the rats were euthanized, the lungs were processed for histological examinations. Paraffin sections were stained with Haematoxylin&Eosin (H&E) for light microscopic observation. Apoptosis was evaluated by caspase-3 immunoreactivity. Data were statistically analyzed using the SPSS software.. In the lung sections stained with H&E, a normal histological structure was observed in group-1, whereas disorganized epithelial cells, hemorrhage, and inflammatory cell infiltration were seen in the alveolar wall in group-2. The histologic structure of the treatment groups was better than that of group-2. Caspase-3(+) apoptotic cells were noticeable in sections of group-2 and were lower in the treatment groups. In group-4, caspase-3 immunostaining was lower than in group-3. In group-2, apoptotic cells were significantly higher than in the other groups (p<0.001).. Based on the histological results, we suggested that both therapies ameliorated the detrimental effects of IR. Caspase-3 immunohistochemistry results also revealed that pre-treatment with enoxaparin gave better results in an IR-induced rat injury model. In further studies, other parameters such as ROS and inflammatory gene expressions should be evaluated for accurate results.

Topics: Animals; Aorta, Abdominal; Apoptosis; Caspase 3; Disease Models, Animal; Enoxaparin; Lung; Lung Injury; Male; Protective Agents; Random Allocation; Rats, Wistar; Reperfusion Injury; Ticagrelor

We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin.. Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction.. Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects.. Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.

Topics: Animals; Apoptosis; Aspirin; Atrial Natriuretic Factor; Disease Models, Animal; Drug Therapy, Combination; Endoglin; Fibrosis; Gene Expression Regulation; Myocardial Infarction; Myocardial Reperfusion Injury; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Proto-Oncogene Proteins c-kit; Rats; Rats, Sprague-Dawley; Stem Cells; Ticagrelor; Ventricular Function, Left; Ventricular Remodeling

Platelets are traditionally considered to be essential components of primary hemostasis. Recent investigations have revealed that platelets can be activated in patients with sepsis and are implicated in the development of sepsis and sepsis-induced-acute kidney injury (SAKI). In the present study, ticagrelor was used to induce a mouse model of SAKI by cecal ligation and puncture. It was found that ticagrelor could inhibit platelet activity, decrease the levels of interleukin-1β and serum creatinine, reduce infiltration of neutrophils in renal tissue, and attenuate cell apoptosis in the kidney. The results suggested that ticagrelor could protect renal function by inhibiting inflammation, recruitment of neutrophils into the kidney, and cell apoptosis in renal tissue. Thus, the findings might provide new strategies for preventing SAKI.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Humans; Male; Mice; Platelet Aggregation Inhibitors; Sepsis; Ticagrelor

Topics: Adenosine; Animals; Disease Models, Animal; Equilibrative Nucleoside Transporter 1; Ischemic Preconditioning, Myocardial; Isolated Heart Preparation; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Purinergic P2Y Receptor Antagonists; Rats, Sprague-Dawley; Ticagrelor

We recently showed that ticagrelor reduced myocardial ischemia-reperfusion injury (IRI) and downregulated galectin-3 in the ischemic myocardium. This study tested the hypothesis that ticagrelor could reduce IRI through the NF-κB pathway. Rats were randomly divided into sham-operated group, placebo group (gastric administration of saline after IRI), ticagrelor group (gastric administration of ticagrelor after left anterior descending artery ligation), dextran sodium sulfate (DSS) group (DSS was added to drinking water 7 days before IRI), and DSS + ticagrelor group (DSS was added to drinking water 7 days before IRI and gastric administration of ticagrelor after left anterior descending artery ligation). Ticagrelor significantly reduced the infarct size and plasma cTnI at 3 and 7 days after IRI, significantly downregulated protein and mRNA expressions of NF-κB and galectin-3, and mRNA expressions of IL-6 and TNF-α in the ischemic area at 24 hours, 3 and 7 days after IRI. Ticagrelor also significantly decreased plasma high-sensitivity C-reactive protein and NT-proBNP levels at 24 hours and 3 days after IRI. Furthermore, pretreatment with DSS blocked the beneficial effects of ticagrelor. Our study indicates that the cardioprotective effect of ticagrelor might be partly mediated by inhibiting the NF-κB pathway in this rat model of IRI.

Topics: Animals; Anti-Inflammatory Agents; C-Reactive Protein; Disease Models, Animal; Galectin 3; Interleukin-6; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Natriuretic Peptide, Brain; NF-kappa B; Peptide Fragments; Rats, Sprague-Dawley; Signal Transduction; Ticagrelor; Troponin I; Tumor Necrosis Factor-alpha

Accumulation of lysosomal waste is linked to neurodegeneration in multiple diseases, and pharmacologic enhancement of lysosomal activity is hypothesized to reduce pathology. An excessive accumulation of lysosomal-associated lipofuscin waste and an elevated lysosomal pH occur in retinal pigment epithelial cells of the ABCA4-/- mouse model of Stargardt's retinal degeneration. As treatment with the P2Y12 receptor antagonist ticagrelor was previously shown to lower lysosomal pH and lipofuscin-like autofluorescence in these cells, we asked whether oral delivery of ticagrelor also prevented photoreceptor loss.. Moderate light exposure was used to accelerate photoreceptor loss in albino ABCA4-/- mice as compared to BALB/c controls. Ticagrelor (0.1%-0.15%) was added to mouse chow for between 1 and 10 months. Photoreceptor function was determined with electroretinograms, while cell survival was determined using optical coherence tomography and histology.. Protection by ticagrelor was demonstrated functionally by using the electroretinogram, as ticagrelor-treated ABCA4-/- mice had increased a- and b-waves compared to untreated mice. Mice receiving ticagrelor treatment had a thicker outer nuclear layer, as measured with both optical coherence tomography and histologic sections. Ticagrelor decreased expression of LAMP1, implicating enhanced lysosomal function. No signs of retinal bleeding were observed after prolonged treatment with ticagrelor.. Oral treatment with ticagrelor protected photoreceptors in the ABCA4-/- mouse, which is consistent with enhanced lysosomal function. As mouse ticagrelor exposure levels were clinically relevant, the drug may be of benefit in preventing the loss of photoreceptors in Stargardt's disease and other neurodegenerations associated with lysosomal dysfunction.

Topics: Administration, Oral; Animals; Disease Models, Animal; Electroretinography; Gene Expression Regulation; Lysosomal Membrane Proteins; Mice; Mice, Inbred BALB C; Neoplasm Proteins; Purinergic P2Y Receptor Antagonists; Retinal Degeneration; Retinal Pigment Epithelium; RNA; Ticagrelor; Tomography, Optical Coherence; Treatment Outcome

The full benefits of myocardial revascularization strategies applied to acute myocardial infarction patients might be reduced by myocardial ischaemia and reperfusion (I/R) injury. It is known that inflammation plays an important role in the pathogenesis of I/R injury and galectin-3, a known inflammatory factor, is actively involved in ischaemia-induced inflammation and fibrosis of various organs. Previous studies demonstrated that anti-platelets therapy with ticagrelor, a new P2Y12 receptor antagonist, could effectively attenuate myocardial I/R injury and I/R injury-related inflammatory responses. It remains unknown whether the cardioprotective effects of ticagrelor are also mediated by modulating myocardial galectin-3 expression.. Our results showed that ticagrelor treatment significantly reduced IA/AAR ratio at 3 and 7 days post I/R, downregulated mRNA and protein expression of galectin-3, as well as mRNA expression of TNF-α and IL-6 in infarct area at 24 h, 3 and 7 days post I/R.. Our results suggest that the cardioprotective effects of ticagrelor might partly be mediated by downregulating galectin-3 expression in infarct area in this rat model of myocardial I/R injury.

Topics: Animals; Anti-Inflammatory Agents; Cytoprotection; Disease Models, Animal; Down-Regulation; Galectin 3; Inflammation Mediators; Interleukin-6; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Rats, Sprague-Dawley; Ticagrelor; Time Factors; Tumor Necrosis Factor-alpha

Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe. Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05).. Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Phosphorylation; Plaque, Atherosclerotic; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Ticagrelor; Vasodilation

P2Y12 antagonists are the standard in antiplatelet therapy but their potential effects on functional myocardial recovery and cardioprotection post-myocardial infarction (MI) are unknown. We investigated in a preclinical model of MI whether ticagrelor and clopidogrel differently affect cardiac repair post-MI.. Pigs either received: (i) clopidogrel (600 mg; 75 mg/qd); (ii) ticagrelor (180 mg; 90 mg/bid); and (iii) placebo control. MI was induced by mid-left anterior descending coronary artery balloon occlusion (60 min) and animals received the maintenance doses for the following 42 days. Serial cardiac magnetic resonance was performed at Day 3 and Day 42 for the assessment of global and regional cardiac parameters. We determined cardiac AMP-activated protein kinase (AMPK), Akt/PKB, aquaporin-4, vascular density, and fibrosis. In comparison to controls, both P2Y12 antagonists limited infarct expansion at Day 3, although ticagrelor induced a further 5% reduction (P < 0.05 vs. clopidogrel) whereas oedema was only reduced by ticagrelor (≈23% P < 0.05). Scar size decreased at Day 42 in ticagrelor-treated pigs vs. controls but not in clopidogrel-treated pigs. Left ventricular ejection fraction was higher 3 days post-MI in ticagrelor-treated pigs and persisted up to Day 42 (P < 0.05 vs. post-MI). Regional analysis revealed that control and clopidogrel-treated pigs had severe and extensive wall motion abnormalities in the jeopardized myocardium and a reduced myocardial viability that was not as evident in ticagrelor-treated pigs (χ2P < 0.05 vs. ticagrelor). Only ticagrelor enhanced myocardial AMPK and Akt/PKB activation and reduced aquaporin-4 levels (P < 0.05 vs. control and clopidogrel). No differences were observed in vessel density and fibrosis markers among groups.. Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.

Topics: AMP-Activated Protein Kinases; Animals; Clopidogrel; Disease Models, Animal; Echocardiography; Fibrosis; Heart Ventricles; Magnetic Resonance Imaging, Cine; Myocardial Infarction; Myocytes, Cardiac; Proto-Oncogene Proteins c-akt; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Signal Transduction; Stroke Volume; Sus scrofa; Ticagrelor; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Adenosine 5'-diphosphate is a key endogenous cell-signaling molecule that can activate P2 purinergic receptor family members. ADP-P2Y signaling is reported to be associated with inflammation, but its function in T cell differentiation and autoimmune diseases pathogenesis is unclear. In this study, we found that the P2Y

Topics: Adenosine; Animals; Autoimmune Diseases; Cell Differentiation; Cells, Cultured; Clopidogrel; Colitis; Diabetes Mellitus, Experimental; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; Interleukin-17; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Th17 Cells; Ticagrelor; Ticlopidine; Trinitrobenzenesulfonic Acid

Ticagrelor is a direct acting and reversibly binding P2Y12 antagonist approved for the prevention of thromboembolic events. Its potential benefits in ischemic stroke have not been investigated sufficiently. Mice were subjected to 2 hours of transient middle cerebral artery occlusion (MCAO). Mice were orally treated with ticagrelor (10 or 30 mg/kg), aspirin (60 mg/kg), or vehicle at 3 and 24 hours before MCAO and 0 and 6 hours after reperfusion. The infarct volume and neurological deficits 22 hours after reperfusion were evaluated. Cerebral blood flow (CBF) within 24 hours after MCAO was monitored. We performed western blotting and in vitro analysis using oxygen-glucose deprivation (OGD) stress in human brain microvessel endothelial cells (HBMVECs) to investigate the protective effects of ticagrelor. Ticagrelor (30 mg/kg) improved neurological deficits, reduced the infarct volume, and improved CBF. It promoted the phosphorylation of endothelial nitric oxide synthase (eNOS) and extracellular signal-regulated kinase 1/2 (ERK1/2) during the early phase after reperfusion. Increased phosphorylation of eNOS and ERK1/2 were also observed in HBMVECs after OGD stress. Ticagrelor attenuate ischemia reperfusion injury possibly via phosphorylation of eNOS and ERK1/2 in endothelial cells. This suggests that ticagrelor has neuroprotective effects via mechanisms other than its antiplatelet action.

Topics: Animals; Brain Infarction; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Humans; Infarction, Middle Cerebral Artery; Mice; Neuroprotective Agents; Nitric Oxide Synthase Type III; Phosphorylation; Purinergic P2Y Receptor Antagonists; Reperfusion Injury; Stroke; Ticagrelor

The P2Y. Ticagrelor, unlike clopidogrel, exhibits endothelial-specific antithrombotic properties and blunts arterial thrombus formation. The additional antithrombotic properties displayed by ticagrelor may explain its greater efficacy in reducing thrombotic events in clinical trials. These findings may provide the basis for new indications for ticagrelor.

Topics: Adenosine; Animals; Blood Coagulation; Blood Platelets; Carotid Artery Injuries; Cells, Cultured; Clopidogrel; Disease Models, Animal; Down-Regulation; Endothelial Cells; Equilibrative Nucleoside Transporter 1; Fibrinolytic Agents; Humans; Male; Mice, Inbred C57BL; Platelet Aggregation Inhibitors; Proteasome Endopeptidase Complex; Proteolysis; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thromboplastin; Thrombosis; Ticagrelor; Ticlopidine; Time Factors; Tumor Necrosis Factor-alpha

Topics: Age of Onset; Animals; Animals, Genetically Modified; Biomarkers; Brain; Carrier Proteins; Corpus Striatum; Dilazep; Dipyridamole; Disease Models, Animal; Disease Progression; Equilibrative Nucleoside Transporter 1; Humans; Huntingtin Protein; Huntington Disease; Mice; Neurons; Rats; Receptor, Adenosine A2A; Ticagrelor

There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated.. Twenty-week-old apolipoprotein-E-deficient mice received standard chow or standard chow supplemented with 0.15% ticagrelor (approximately 270 mg/kg/day) for 25 weeks. The lesion area was evaluated in the aortic sinus by Movat's pentachrome staining and lesion composition, thickness of the fibrous cap, and size of the necrotic core evaluated by morphometry. RAW 264.7 macrophages were serum starved and treated with ticagrelor in vitro for the detection and quantification of apoptosis. In addition, oxLDL uptake in RAW 264.7 macrophages was evaluated.. A trend toward the reduction of total lesion size was detected. However, data did not reach the levels of significance (control, n=11, 565,881 μm(2) [interquartile range {IQR} 454,778-603,925 μm(2)] versus ticagrelor, n=13, 462,595 μm(2) [IQR 379,740-546,037 μm(2)]; P=0.1). A significant reduction in the relative area of the necrotic core (control, n=11, 0.46 [IQR 0.4-0.51] versus ticagrelor, n=13, 0.34 [IQR 0.31-0.39]; P=0.008), and a significant increase in fibrous caps thickness (control, n=11, 3.7 μm [IQR 3.4-4.2 μm] versus ticagrelor, n=13, 4.7 [IQR 4.3-5.5 μm], P=0.04) were seen in ticagrelor-treated mice. In vitro studies demonstrated a reduction in apoptotic RAW 264.7 macrophages (control 0.07±0.03 versus ticagrelor 0.03±0.03; P=0.0002) when incubated with ticagrelor. Uptake of oxLDL in RAW 264.7 was significantly reduced when treated with ticagrelor (control 9.2 [IQR 5.3-12.9] versus ticagrelor 6.4 [IQR 2.5-9.5], P=0.02).. The present study demonstrates for the first time a plaque-stabilizing effect of ticagrelor in a model of advanced vascular disease, potentially induced by a reduction of oxLDL uptake or an inhibition of apoptosis as seen in vitro.

Topics: Adenosine; Administration, Oral; Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Disease Models, Animal; Dose-Response Relationship, Drug; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Structure-Activity Relationship; Ticagrelor

In addition to P2Y12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function.. Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%). All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A4 levels.. Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect.

Topics: Adenosine; Administration, Oral; Animals; Apoptosis; Cardiotonic Agents; Clopidogrel; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Injections, Intraperitoneal; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Purinergic P2Y Receptor Antagonists; Rats, Sprague-Dawley; Signal Transduction; Ticagrelor; Ticlopidine; Time Factors; Ventricular Function, Left; Ventricular Remodeling

Abstract Platelets play an important role in abdominal sepsis and P2Y12 receptor antagonists have been reported to exert anti-inflammatory effects. Herein, we assessed the impact of platelet inhibition with the P2Y12 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis. Wild-type C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Animals were treated with ticagrelor (100 mg/kg) or vehicle prior to CLP induction. Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified. Flow cytometry was used to determine expression of platelet-neutrophil aggregates, neutrophil activation and CD40L expression on platelets. CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50% in ticagrelor-treated animals. Moreover, ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41%. Notably, ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals. In addition, ticagrelor reduced platelet shedding of CD40L in septic mice. Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists, such as ticagrelor, in the management of patients with abdominal sepsis.

Topics: Adenosine; Animals; Blood Platelets; Chemokines, CXC; Disease Models, Animal; Lung Injury; Macrophage-1 Antigen; Male; Mice; Neutrophil Infiltration; Neutrophils; Platelet Aggregation; Pulmonary Edema; Purinergic P2Y Receptor Antagonists; Sepsis; Ticagrelor

In the present study, we aimed to deterimine the dose-related effects of ticagrelor, the first reversible inhibitor of the P2Y12 receptor, found in smooth muscle cells as well as platelets, during neointimal hyperplasia in a rabbit carotid anastomosis model.. This study was an experimental, prospective, randomized controlled study including 20 New Zealand white female rabbits (6-months old; weighing 2300 ± 300 g). Under general anaesthesia, the rabbits underwent transection of the right carotid artery and subsequent anastomosis of both ends. The study animals were divided into the following 4 groups: T1 (ticagrelor 5 mg/kg, orally, daily), T2 (ticagrelor 10 mg/kg, orally, daily), T3 (ticagrelor 20 mg/kg, orally, daily) and control (no ticagrelor treatment). The single oral doses were administered in phosphate-buffered saline. The control group received sterile phosphate-buffered saline (2 ml/kg/day, orally) for 3 weeks postoperatively. At the end of the study, the animals were killed, and the anastomosed segment of the right carotid artery and part of the left carotid artery were excised from each animal. Antibodies against transforming growth factor-β were used in staining of arterial sections, which was followed by histomorphological and immunohistochemical studies.. The median intimal thickness (2.0 ± 0.14 µm left vs 73.4 ± 35.8 µm anastomosed right arteries; P <0.05), the median medial thickness (70.8 ± 5.6 µm left vs 92.3 ± 4.5 µm anastomosed right arteries; P <0.05) and the index ratio of intimal thickness to medial thickness (0.03 ± 0.00 left vs 0.8 ± 0.35 anastomosed control right arteries; P <0.05) increased significantly in the anastomosed right arteries compared with the left carotid arteries in the control group. In the treatment groups, the intimal thickness (73.4 ± 35.8 µm in control group vs T1 32.7 ± 19;1 µm, T2 1.9 ± 0.09 µm and T3 2.2 ± 0.5 µm; P = 0.047, P = 0.009 and P = 0.009, respectively), carotid artery intima/media ratio (0.8 ± 0.35 in control group vs T1 0.4 ± 0.2, T2 0.03 ± 0.01 and T3 0.03 ± 0.01 in ticagrelor groups; P = 0.028, P = 0.009 and P = 0.009, respectively) and medial thickness (92.3 ± 4.5 µm in control group vs T2 65.6 ± 7.1 and T3 66.1 ± 7.6 µm; P = 0.009 and P = 0.009, respectively) decreased significantly in the anastomosed right arteries.. This study indicates that effective doses (10 and 20 mg/kg, daily) of the antiplatelet agent ticagrelor in a rabbit model may be beneficial in prevention of intimal hyperplasia. Restenosis due to intimal hyperplasia has been high. Ticagrelor has also been linked to inhibition of smooth muscle cell proliferation and, hence, reduced intimal hyperplasia.

Topics: Adenosine; Anastomosis, Surgical; Animals; Biopsy; Carotid Arteries; Carotid Stenosis; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hyperplasia; Immunohistochemistry; Neointima; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Rabbits; Receptors, Purinergic P2Y12; Recurrence; Ticagrelor; Transforming Growth Factor beta

A routine secondary pharmacology screen indicated that reversibly binding oral P2Y(12) receptor antagonist ticagrelor could inhibit adenosine uptake in human erythrocytes, suggesting that ticagrelor may potentiate adenosine-mediated responses in vivo. The aim of this study was to further characterize the adenosine uptake inhibition in vitro and study possible physiological consequences of adenosine uptake inhibition by ticagrelor in an anesthetized dog model of coronary blood flow compared to dipyridamole.. We measured [2-3H]adenosine uptake in purified human erythrocytes and several cell lines in the presence of ticagrelor or the known uptake inhibitor dipyridamole as a comparator. Using an open-chest dog model (beagles), we measured the left anterior descending (LAD) coronary artery blood flow during reactive hyperemia after 1 minute occlusion or intracoronary infusion of adenosine before and after administration of vehicle, ticagrelor, or dipyridamole (each n = 8). Ticagrelor concentration-dependently inhibited adenosine uptake in human erythrocytes and in cell lines of rat, canine, or human origin. In the dog model, ticagrelor and dipyridamole dose-dependently augmented reactive hyperemia after LAD occlusion, as assessed by percentage repayment of flow debt relative to control (both Ps < .05). Ticagrelor and dipyridamole also dose-dependently augmented intracoronary adenosine-induced increases in LAD blood flow relative to control (both Ps < .05).. Ticagrelor inhibits adenosine uptake in vitro and subsequently augments cardiac blood flow in a canine model of reactive hypoxia- or adenosine-induced blood flow increases. These findings suggest that ticagrelor may have additional benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation.

Topics: Acute Coronary Syndrome; Adenosine; Animals; Cell Line; Cell Line, Tumor; Coronary Circulation; Dipyridamole; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Erythrocytes; Female; Humans; Hyperemia; Male; Purinergic P2Y Receptor Antagonists; Rats; Ticagrelor

Reperfusion therapy for myocardial infarction is limited by significant re-occlusion rates and less-than-optimal myocardial tissue perfusion. It was the objective of this study to assess and compare the effect of ticagrelor, the first reversibly binding oral P2Y12 receptor antagonist, with that of clopidogrel, in conjunction with thrombolytic therapy, on platelet aggregation, thrombus formation, and myocardial perfusion in a canine model. Thrombus formation was induced by electrolytic injury and blood flow was measured with a Doppler ultrasonic flowmeter. All animals received tissue plasminogen activator (tPA) (1 mg/kg over 20 min); 10 animals received clopidogrel (10 mg/kg IV bolus over 5 min), 10 animals received ticagrelor initiated with a 1-min bolus (75 microg/kg/min), followed by continuous infusion (10 microg/kg/min) for 2 h, and 10 animals received IV saline. Re-occlusion rate and cyclic flow variation decreased with ticagrelor compared to saline groups (p<0.05). Adenosine phosphate (ADP)-induced platelet aggregation decreased with ticagrelor (1.9% +/- 2.67) and clopidogrel (1.11% +/- 2.0) vs. saline (26.3% +/- 23.5, p<0.05) at the end of adjunctive therapy. Bleeding time increased in the clopidogrel compared to the ticagrelor group (p=0.01). Infarct size was reduced with ticagrelor compared to the clopidogrel and saline groups (p<0.05). Blood flow remained significantly below baseline values at 20 min after tPA administration in the saline and clopidogrel groups but not in the ticagrelor group. In conclusion, in a dog coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation; prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and cyclic flow variation; and significantly decreases infarct size and rapidly restores myocardial tissue perfusion.

Topics: Adenosine; Animals; Bleeding Time; Blood Coagulation; Clopidogrel; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Drug Therapy, Combination; Echocardiography; Female; Fibrinolytic Agents; Laser-Doppler Flowmetry; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Recurrence; Thrombolytic Therapy; Ticagrelor; Ticlopidine; Time Factors; Tissue Plasminogen Activator

Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y(12) inhibition required to inhibit neointima formation following vascular injury.. Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y(12)+/+ and P2Y(12)-/- mice. Neointima formation in FeCl(3)-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y(12)-/- mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921±22 749 μm(2), versus ticagrelor, 3705±2600 μm(2); P<0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective.. Ticagrelor effectively and reversibly inhibits P2Y(12)-mediated platelet function and thrombosis in mice. P2Y(12) inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y(12) inhibition in preventing restenosis.

Topics: Adenosine; Animals; Bleeding Time; Blood Coagulation; Blood Platelets; Carotid Artery Injuries; Carotid Artery, Common; Carotid Stenosis; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; P-Selectin; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Tunica Intima

Platelet activation and thrombus renewal are keys to intraluminal thrombus formation and progression of abdominal aortic aneurysms (AAA). This study explored the ability of AZD6140, a P2Y(12) receptor antagonist, to inhibit platelet activation and prevent aneurysm development in a rat experimental model of AAA.. Aortic aneurysms were induced by implanting a segment of sodium dodecyl sulfate-decellularized guinea pig aorta in rat aortas. One day later, rats were randomized to AZD6140 (10 mg/kg twice daily by mouth) or diluent (n = 23 per group) for either 10 (n = 18) or 42 days (n = 28). Adenosine diphosphate (ADP)-mediated platelet aggregation, aneurysm expansion, intraluminal thrombus formation, inflammatory infiltration, matrix metalloproteinase-9 (MMP-9) expression, and smooth muscle cell colonization were measured.. AZD6140 inhibited ADP-induced platelet aggregation in vivo for 12 hours, justifying twice-daily administration in rats. The spontaneous increase in aortic diameter shown in the aneurysmal model (2.22 +/- 0.56 mm at day 10 vs 5.21 +/- 1.22 mm at day 42) was reduced with AZD6140 (3.61 +/- 1.46 mm at day 42, P < .01). This beneficial effect was associated with a significant reduction of thrombus development, platelet CD41 expression (P < .05), and leukocyte infiltration of the mural thrombus at days 10 and 42 (P < .01). MMP-9 expression correlated with mural thrombus area and was significantly reduced by AZD6140 (P < .05). AZD6140 limited elastic fiber degradation (P < .05) and enhanced progressive colonization of the thrombus by smooth muscle cells at day 42 (P < .01).. These data suggest that inhibition of platelet activation limits intraluminal thrombus biologic activities, thereby impairing aneurysm development.

Topics: Adenosine; Adenosine Diphosphate; Animals; Aorta; Aortic Aneurysm, Abdominal; Blood Platelets; Disease Models, Animal; Disease Progression; Elastic Tissue; Guinea Pigs; Inflammation; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Rats; Rats, Inbred Lew; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thrombosis; Ticagrelor; Time Factors; Transplantation, Heterologous

Ticagrelor (AZD6140), the first reversibly binding oral P2Y(12) receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y(12) for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y(12) and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y(12), and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets. In rat and dog models of thrombosis/hemostasis, there was greater separation between doses that provided antithrombotic effect and those that increased bleeding for ticagrelor compared with clopidogrel and compound 072, a chemical compound indistinguishable from the prasugrel parent compound. The ratio of dose resulting in 3-fold increase in bleeding time to dose resulting in 50% restoration of blood flow in rats was 9.7 for ticagrelor compared with 2.0 for clopidogrel and 1.4 for compound 072. Similar results were observed in dogs. Our findings suggest that reversibility of P2Y(12) binding with ticagrelor may account for the greater separation between antithrombotic effects and increased bleeding compared with the irreversible binding of clopidogrel and prasugrel.

Topics: Adenosine; Animals; CHO Cells; Clopidogrel; Cricetinae; Cricetulus; Disease Models, Animal; Dogs; Hemostasis; Humans; Piperazines; Platelet Aggregation; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2Y12; Thiophenes; Thrombosis; Ticagrelor; Ticlopidine; Transfection