thromboxane-a2 and Brain-Ischemia

Mild to moderate hypothermia (32-35 degrees C) is the first treatment with proven efficacy for postischemic neurological injury. In recent years important insights have been gained into the mechanisms underlying hypothermia's protective effects; in addition, physiological and pathophysiological changes associated with cooling have become better understood.. To discuss hypothermia's mechanisms of action, to review (patho)physiological changes associated with cooling, and to discuss potential side effects.. Review article.. None.. A myriad of destructive processes unfold in injured tissue following ischemia-reperfusion. These include excitotoxicty, neuroinflammation, apoptosis, free radical production, seizure activity, blood-brain barrier disruption, blood vessel leakage, cerebral thermopooling, and numerous others. The severity of this destructive cascade determines whether injured cells will survive or die. Hypothermia can inhibit or mitigate all of these mechanisms, while stimulating protective systems such as early gene activation. Hypothermia is also effective in mitigating intracranial hypertension and reducing brain edema. Side effects include immunosuppression with increased infection risk, cold diuresis and hypovolemia, electrolyte disorders, insulin resistance, impaired drug clearance, and mild coagulopathy. Targeted interventions are required to effectively manage these side effects. Hypothermia does not decrease myocardial contractility or induce hypotension if hypovolemia is corrected, and preliminary evidence suggests that it can be safely used in patients with cardiac shock. Cardiac output will decrease due to hypothermia-induced bradycardia, but given that metabolic rate also decreases the balance between supply and demand, is usually maintained or improved. In contrast to deep hypothermia (

Topics: Acidosis; Apoptosis; Body Temperature Regulation; Brain Edema; Brain Ischemia; Calpain; Critical Care; Epilepsy; Free Radicals; Genes, Immediate-Early; Humans; Hypothermia, Induced; Infections; Inflammation; Ion Pumps; Mitochondria; Reperfusion Injury; Thrombosis; Thromboxane A2

Topics: Animals; Brain Ischemia; Calcium Channel Blockers; Drugs, Chinese Herbal; Free Radical Scavengers; Humans; Phytotherapy; Reperfusion Injury; Thromboxane A2

Topics: Brain Ischemia; Epoprostenol; Humans; Leukotriene B4; SRS-A; Thromboxane A2

It has been suggested that daily intake of aspirin is associated with a reduction of cognitive decline, both in normal and in demented subjects, but the mechanism is unclear. We have therefore studied the relationship between thromboxane (TX) A(2) biosynthesis, as reflected by the urinary excretion of 11-dehydro-TXB(2), and the presence of dementia in patients after acute stroke.. Patients from the Rotterdam Stroke Databank were screened for dementia between 3 and 9 months after stroke. Patients had a full neurological examination, neuropsychological screening, and, if indicated, extensive neuropsychological examination. Criteria used for the diagnosis of dementia were from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (Revised). Urine samples were taken at the time of screening. Urinary 11-dehydro-TXB(2) was measured by means of a previously validated radioimmunoassay.. Dementia was diagnosed in 71 patients, and urine samples were available for 62. Median value (range) of 11-dehydro-TXB(2) was 399 (89 to 2105) pmol/mmol creatinine for demented patients versus 273 (80 to 1957) for 69 controls with stroke but without dementia (P=0.013). No difference was found between 44 patients with vascular dementia, 404 (89 to 2105) pmol/mmol creatinine, and 18 patients with Alzheimer's disease plus cerebrovascular disease, 399 (96 to 1467) pmol/mmol creatinine (P=0.68). In a stepwise logistic regression analysis, in which possible confounders such as use of antiplatelet medication, cardiovascular risk factors, and type of stroke were taken into account, increased urinary excretion of 11-dehydro-TXB(2) remained independently related to the presence of dementia (OR 1.12, 95% CI 1.03 to 1.22 per 100 pmol/mmol creatinine). The difference in metabolite excretion rates between demented and nondemented patients was most prominent within the subgroup of ischemic stroke patients who received aspirin (P<0.01).. Increased thromboxane biosynthesis in the chronic phase after stroke is associated with the presence of but not the type of poststroke dementia. It is particularly apparent in patients on aspirin, thereby suggesting the involvement of extraplatelet sources of TXA(2) production in this setting.

Topics: Aged; Aspirin; Biomarkers; Blood Platelets; Brain Ischemia; Cerebral Hemorrhage; Chronic Disease; Cognition; Creatinine; Dementia, Vascular; Female; Humans; Male; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Platelet aggregation was examined in 43 patients after ischemic stroke and in 16 healthy subjects using multiparametric aggregation index (MAI). The value of MAI was significantly higher in stroke patients (3.15 in patients and 0.92 l/mumol in controls, p < 0.0001). Patients who had increased MAI (n = 26) were treated with a daily dose of 100 mg acetilsalicylic acid (ASA). Platelet activity was measured before and on the 7th and 28th day of treatment measuring three parameters: MAI, spontaneous dysaggregation and collagen induced aggregation. All 3 methods showed a significant decrease in platelet aggregation on the 7th day of treatment, but further changes were not found on the 28th day. Serum levels of thromboxane-A2 (TXA2) and prostacycline (PGI2) metabolites (TXB2 and 6-keto-prostaglandin-F1 alpha) were determined before and on the 28th day of treatment. The effect of 100 mg ASA per day proved to be selective: comparing the serum levels before and after treatment, a significant decrease of TXB2 concentration was found without changes in the concentration of 6-keto-prostaglandin-F1 alpha. Evaluating MAI and the value of dysaggregation might reflect ineffectiveness of antiplatelet therapy in patients not responding to a daily dose of 100 mg of ASA. For these patients the increase of the daily dose of ASA, or changing to another antiplatelet drug might be recommended.

Topics: Aged; Aged, 80 and over; Aspirin; Blood Coagulation Tests; Brain Ischemia; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Thromboxane A2; Thromboxane B2

The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia.. Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100. The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameter. Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia.

Topics: Animals; Biomarkers; Brain Ischemia; Epoprostenol; Glutathione Peroxidase; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Male; Models, Theoretical; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein beta Subunit; Thromboxane A2

Eicosanoids may play a role in ischemic stroke. However, the associations of variants in cyclooxygenase (COX) pathway genes and interaction among these variants with carotid plaque vulnerability are not fully understood. In present study, twelve variants in COX pathway genes were examined using matrix-assisted laser desorption ionization time-of-flight mass spectrometry method in 396 patients with ischemic stroke and 291 controls. Platelet aggregation, platelet-leukocyte aggregates, and urine 11-dehydrothromboxane B2 (11-dTxB2) were also measured. According to the results of carotid high-resolution B-mode ultrasound, the patients were stratified into the following groups [i.e., non-carotid plaque and carotid plaque. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP)]. Additionally, gene-gene interactions were analyzed to assess whether there was any interactive role for assessed variants in affecting carotid plaque vulnerability, platelet activation and 11-dTxB2 levels. There were no significant differences in the frequencies of genotypes of the twelve variants between patients and controls. Among 396 patients, 294 cases (74.2%) had carotid plaques (106 had ELP, 188 had EGP). Frequency of PTGS2 rs20417CC, TXAS1 rs2267679TT, TXAS1 rs41708TT, PTGIS rs5602CC, and TXA2R rs1131882TT genotype was significantly higher in patients with plaque compared with patients without plaque, or in patients with ELP compared with patients with EGP. 11-dTxB2 levels, platelet aggregation and platelet-leukocyte aggregates were significantly higher in patients with ELP compared with patients without plaque or with EGP. Multivariate logistic regression analysis revealed that PTGS2 rs20417CC, TXA2R rs1131882TT, and high-risk interaction among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were independently associated with the risk of ELP after adjusting for confounding variables. The variants in COX pathway genes and the high-risk interactions among variants in PTGS2 rs20417, TXA2R rs1131882 and TXAS1 rs41708 were associated with high 11-dTxB2 and platelet activation, and independently associated with the risk of carotid plaque vulnerability. These variants might be potential markers for plaque instability.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Carotid Arteries; Case-Control Studies; Cyclooxygenase 2; Female; Humans; Male; Middle Aged; Plaque, Atherosclerotic; Platelet Activation; Polymorphism, Single Nucleotide; Receptors, Thromboxane A2, Prostaglandin H2; Stroke; Thromboxane A2; Thromboxane-A Synthase

Thromboxane A2 (TXA2) can induce the platelet aggregation and lead to thrombosis. This will cause the low-reflow phenomenon after ischemic stroke and aggravate the damage of brain issues. Therefore, it is potential to develop the drugs inhibiting TXA2 pathway to treat cerebral ischemia.. This study aims to prove the protective effect of N2 (4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoic acid) on focal cerebral ischemia and reperfusion injury through platelet aggregation inhibition.. Middle cerebral artery occlusion/reperfusion (MCAO/R) is used as the animal model. Neurological deficit score, Morris water maze, postural reflex test, Limb-use asymmetry test, infarct volume, and water content were performed to evaluate the protective effect of N2 in MCAO/R rats. 9, 11-dieoxy-11α, 9α-methanoepoxyprostaglandin F2α (U46619) or adenosine diphosphate (ADP) was used as the inducer of platelet aggregation.. N2 can improve the motor function, learning and memory ability in MCAO/R rats while reducing the infarct volume. N2 can inhibit TXA2 formation but promote PGI2, and can inhibit platelet aggregation induced by U46619 and ADP. Further, N2 inhibits thrombosis with a minor adverse effect of bleeding than Clopidogrel. In conclusion, N2 can produce the protective effect on MCAO/R brain injury through inhibiting TXA2 formation, platelet aggregation and thrombosis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arteriovenous Shunt, Surgical; Blood Coagulation; Brain; Brain Ischemia; Edema; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Imidazoles; Male; Maze Learning; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Stroke; Thrombosis; Thromboxane A2; Vanillic Acid

Toona sinensis Roem. (Meliaceae; Toona sinensis; Chinese toon) is a type of arbor that is widely distributed in Asia. The fruits of Toona sinensis Roem has been traditionally recognized for treatment of cerebrovascular diseases. To evaluate the potential clinical use of the fruits of Toona sinensis Roem, we determined the dose dependence of the neuroprotective efficacy in a focal cerebral ischemic reperfusion model of rats and explored the underlying mechanisms.. Rats were subjected to occlusion of the middle cerebral artery (MCAO) by a nylon filament and treated with different doses (20mg/kg and 30 mg/kg) of n-butanol soluble fraction of the water extract of Chinese toon fruit or the vehicle for 1 week before induction of ischemia, s.i.d... n-Butanol soluble fraction of the water extract of Chinese toon fruit reduced in a dose-dependent manner the ischemia-induced cerebral infarct and edema volume and attenuated neurological deficits observed at 6h point after ischemia. n-Butanol soluble fraction of the water extract of Chinese toon fruit reduced the levels of nitrate, nitrite, lipid peroxidation, cyclooxygenase-1, thromboxane in post-ischemic brain. n-Butanol soluble fraction of the water extract of Chinese toon fruit adjusted the elevation of the activity of glutathione peroxidase and superoxide dismutase in ischemic brain.. The present study was the first evidence of effectiveness of n-butanol soluble fraction of the water extract of Chinese toon fruit in the rat stroke models, as it reduced infarct volume, inhibited the oxidative stress and inflammation.

Topics: 1-Butanol; Animals; Brain Ischemia; Epoprostenol; Fruit; Gene Expression Regulation; Glutathione Peroxidase; Inflammation; Male; Malondialdehyde; Meliaceae; Oxidative Stress; Plant Extracts; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thromboxane A2; Water

Thromboxane A2 (TXA2) promotes ischemic stroke injury and has strong effects in vascular contraction and vascular endothelial cell dysfunction. Agents that reduce TXA2 production have potential for ameliorating neural injury in ischemic stroke. Thromboxane synthetase (TXS) is essential for TXA2 production, and TXS inhibitors have been developed as drugs for the prevention and treatment of stroke. However, ozagrel, a typical TXS inhibitor currently in clinical use, must be delivered via intravenous injection (I.V.). N2, 4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate, is a potential thromboxane synthetase (TXS) inhibitor, which is being developed as an orally available formulation. The aim of this study was to investigate the effects of N2 on focal cerebral ischemia-reperfusion injury and related mechanisms. Neurological deficits, a Y-maze test and infarct volume were measured to evaluate the effects of N2 post-treatment on middle cerebral artery occlusion (MCAO)-induced ischemia/reperfusion (I/R) injury in rats. Furthermore, the influence of N2 on U46619-induced rat aorta contraction was investigated ex vivo. Moreover, we investigated the protective effects of N2 on rat brain microvessel endothelial cells (RBMECs) in hypoxia/deoxygenating (H/R) induced by Na2S2O4 in vitro. Cell viability and TXA2 biosynthesis were measured by 3-(4, 5-dimethylthiazol-2-yl)- 195 2, 5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assay (ELISA) assays, respectively. The results showed that N2 treatment effectively improves performance in neurological deficit and the Y-maze test and reduces the infarct volume in I/R rats. U46619-induced rat aorta contraction was inhibited by N2 ex vivo. Furthermore, N2 incubation improved the morphology of RBMECs, increased cell viability, and suppressed TXA2 production by inhibiting TXS during H/R damage. In summary, this study demonstrated that N2 was neural protective in focal cerebral I/R injury, which might be associated with the effects of N2 on endothelium protection and vascular contraction inhibition. In depth, the mechanisms underlying this phenomenon might be the influence of N2 on TXA2 production targeting TXS.

Topics: Animals; Brain Ischemia; Imidazoles; In Vitro Techniques; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Thromboxane A2; Vanillic Acid

Neuroinflammation plays pivotal roles in the progression of cerebral ischemia injury. Prostaglandins (PGs) as the major inflammatory mediators in the brain participate in the pathophysiological processes of cerebral ischemia injury. Cyclooxygenase-2 (COX2) is the rate-limiting enzyme of PGs, and thus it is necessary to characterize of the expression patterns of COX2 and its downstream products at the same time in a cerebral ischemia/reperfusion (I/R) model.. The levels of prostacyclin (PGI2) and thromboxane (TXA2) and the expression of COX2 were detected in the rat hippocampus at different time points after reperfusion (30 min, 2 h, 6 h, 24 h, 48 h, 7 d, and 15 d).. The COX2 mRNA and protein expressions in hippocampus both remarkably increased at 30 min, and peaked at 7 d after global cerebral I/R compared with the sham-operated group. The level of PGI2 significantly increased at 2 h after reperfusion, with a peak at 48 h, but was still significantly higher than the sham-operated animals at 15 d. TXA2 level decreased at 30 min and 2 h after reperfusion, but significantly increased at 6 h and peaked at 48 h. PGI2/TXA2 ratio increased at 30 min after reperfusion, and peaked at 48 h compared with the sham-operated animals.. I/R injury significantly increased the COX2 expression, PGI2 and TXA2 levels, and the PGI2/TXA2 ratio in rat hippocampus in a time-dependent manner. As a consequence, the increased PGI2 level and PGI2/TXA2 ratio may represent a physiological mechanism to protect the brain against the neuronal damage produced by I/R injury.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Cyclooxygenase 2; Hippocampus; Male; Malondialdehyde; Maze Learning; Memory; Prostaglandins I; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Thromboxane A2

We tested the hypothesis that the phytoestrogen genistein protects the brain against ischemic stroke by improving the circulatory function in terms of reduced production of thromboxane A2 and leukocyte-platelet aggregates, and of preserved vascular reactivity. Ischemia-reperfusion (90 min-3 days, intraluminal filament) was induced in male Wistar rats, and functional score and cerebral infarct volume were the end points examined. Genistein (10mg/kg/day) or vehicle (β-cyclodextrin) was administered at 30 min after ischemia or sham-operation. Production of thromboxane A2 and leukocyte-platelet aggregates, as well as reactivity of carotid artery to U-46619 (thromboxane A2 analogue) and to platelet releasate was measured. At 3 days post-ischemia, both improvement in the functional examination and reduction in the total infarct volume were shown in the ischemic genistein-treated group. Genistein significantly reverted both the increased thromboxane A2 concentration and the increased leukocyte-platelet aggregates production found in samples from the ischemic vehicle-treated group. Both U-46619 and platelet releasate elicited contractions of the carotid artery, which were significantly lower in the ischemic vehicle-treated group. Genistein significantly restored both the decreased U-46619- and the decreased platelet releasate-elicited contractile responses. In conclusion, genistein protects the brain against an ischemia-reperfusion challenge, at least in part, by its beneficial effects on the circulatory function.

Topics: Animals; Brain Ischemia; Genistein; Male; Neuroprotective Agents; Phytoestrogens; Platelet Aggregation; Rats; Rats, Wistar; Stroke; Thromboxane A2

The aim of the study was to determine the quantity of produced mediators of inflammation (cytokines and eicosanoids), during carotid endarterectomy (CEA), which are factors of ischemic damage of the brain.. Two groups (A and B) of 15 patients each, with internal carotid backpressure >30 mmHg were operated in our institution. We did not use a shunt in Group A during CEA and group B was operated upon with a shunt. Plasma concentrations of Interleukin-1b (IL-1b), Thromboxane B2 (TXB2), Prostaglandin E2 (PGE2) and tumor necrosis factor-a (TNFa) were measured by enzyme-linked immunosorbent assay (ELISA) technique.. We measured gradual increase of levels of IL-1b and TXB2 during cross-clamping and during reperfusion in group A (P<0.05). The levels of TNFa increased only during reperfusion (P<0.05). The concentration of IL-1b and TNFa remained almost stable in group B, whereas the concentration of TXB2 reduced but not significantly (P>0.05). The levels of PGE2 remained stable in both groups.. We should consider the increase of proinflammatory mediators during carotid cross-clamping when no shunt is used. The critical concentration of these mediators that threaten the brain's vitality is not yet detected. However, the clinical significance of this is unclear, since there were no perioperative strokes.

Topics: Brain Ischemia; Carotid Stenosis; Constriction; Dinoprostone; Endarterectomy, Carotid; Enzyme-Linked Immunosorbent Assay; Female; Greece; Humans; Inflammation Mediators; Interleukin-1beta; Male; Thromboxane A2; Tumor Necrosis Factor-alpha; Up-Regulation

Prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet aggregation and leukocyte activation, is crucial in vascular diseases such as stroke. Prostacyclin synthase (PGIS) is the key enzyme for PGI2 synthesis. Although expression of PGIS was noted in the brain, its role in ischemic insult remains unclear. Here we reported the temporal and spatial expression of PGIS mRNA and protein after 60-min transient ischemia. Northern blot and in situ hybridization revealed a delayed increase of PGIS mRNA in the ischemic cortex at 24- to 72-h after ischemia; PGIS was detected mainly in the ipsilateral penumbra area, pyriform cortex, hippocampus, and leptomeninges. Western blot and immunohistochemical analysis revealed that PGIS proteins were expressed temporally and spatially similar to PGIS mRNA. PGIS was heavily colocalized with PECAM-1 to endothelial cells at the leptomeninges, large and small vessels, and localized to neuronal cells, largely at the penumbra area. A substantial amount of PGIS was also detected in the macrophage and glial cells. To evaluate its role against ischemic infarct, we overexpressed PGIS by adenoviral gene transfer. When infused 72 h before ischemia (- 72 h), Adv-PGIS reduced infarct volume by approximately 50%. However, it had no effect on infarct volume when infused immediately after ischemia (0 h). Eicosanoid analysis revealed selective elevation of PGI2 at - 72 h while PGI2 and TXB2 were both elevated at 0 h, altering the PGI2/thromboxane A2 (TXA2) ratio from 10 to 4. These findings indicate that PGIS protects the brain by enhancing PGI2 synthesis and creating a favorable PGI2/TXA2 ratio.

Topics: Animals; Brain; Brain Ischemia; Cytochrome P-450 Enzyme System; Epoprostenol; Gene Expression Regulation; Intramolecular Oxidoreductases; Kinetics; Rats; Reperfusion Injury; RNA, Messenger; Thromboxane A2; Tissue Distribution

Compliance with antiplatelet therapy is essential for the efficiency of secondary prevention of ischemic stroke. The objective of this study was to evaluate adherence to aspirin treatment in patients with ischemic stroke.. We studied outpatients of 5 neurological ambulatory centers in an urban city, Valencia, all with a history of ischemic stroke who had received aspirin for at least 6 months. A personal interview was carried out in all cases, during which the patients were questioned about adherence to treatment. Platelet thromboxane A2 synthesis was assessed in a single laboratory for the biochemical determination in all patients.. A total of 73 patients (mean age 67) were studied, with a mean duration of aspirin therapy of 25.4 months (range 6-144 months). Sixty-six patients (90.4%) were included in laboratory tests. All showed inhibition of thromboxane A2 synthesis, consistent with adherence to treatment.. Aspirin compliance was found to be excellent. All the patients who presented themselves for laboratory tests were taking aspirin. Even if the patients who failed to show up for laboratory testing are regarded as noncompliants, at least 90% of all patients were compliants--in agreement with the findings of the recent literature. Personal interview plus biochemical determination of platelet thromboxane A2 synthesis seem adequate for assessing adherence to aspirin.

Topics: Adult; Aged; Ambulatory Care; Aspirin; Brain Ischemia; Female; Follow-Up Studies; Health Care Surveys; Humans; Male; Middle Aged; Patient Compliance; Platelet Aggregation Inhibitors; Stroke; Thromboxane A2

Inhibition of erythrocyte (RBC) promotion of platelet reactivity could improve the antiplatelet effect of aspirin (ASA). We tested different ASA regimens for optimal inhibition of platelets and the effects of RBC in patients with a history of vascular diseases. Collagen-induced platelet activation (14C-5HT, TXA2 release) and platelet recruitment (proaggregatory activity of cell-free releasates from activated platelets) were measured in PRP, platelet-RBC (Hct 40%), and whole blood (WB) in 206 patients initially on 200-300-mg ASA/day. Their regimen was modified to biweekly 500 mg (loading dose, L) plus daily or twice-daily low-dose ASA (50 or 100 mg). TXA2 was inhibited with all regimens. Percentage of patients with suboptimal inhibition of platelet recruitment in WB was 200-300 ASA/day (41%), L-50/day (87%), L-100/day (58%), L-50/twice-daily (39%), and L-100/twice-daily (20%; P < 0.05 vs other regimens). 14C-5HT release was inhibited to the greatest extent with L-100/twice-daily in PRP + RBC or WB (P < 0.05 vs other regimens) due to greater inhibition of the RBC prothrombotic effect. Compared with other ASA regimens, L-100 twice-daily (equivalent to 221-mg ASA/day in the 14-day cycle), reduced by >50% the proportion of patients with suboptimal inhibition of platelet recruitment in WB and inhibited 14C-5HT release to the greatest extent.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Brain Ischemia; Collagen; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythrocytes; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Serotonin; Thromboxane A2

Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F2alpha (PGF2alpha) on cerebral microvascular cells.. Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2alpha on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF2alpha and possible involvement of thromboxane in 8-iso-PGF2alpha-induced cytotoxicity were determined.. 8-Iso-PGF2alpha induced time- and concentration-dependent endothelial cell death (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF2alpha induced periventricular damage, which was attenuated by CGS12970 pretreatment.. These data disclose a novel action of 8-iso-PGF2alpha involving TXA2 in oxidant stress-induced cerebral microvascular injury and brain damage.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Cell Death; Cell Survival; Cells, Cultured; Dinoprost; Dinoprostone; DNA Fragmentation; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; F2-Isoprostanes; In Vitro Techniques; Injections, Intraventricular; Isoprostanes; L-Lactate Dehydrogenase; Microcirculation; Muscle, Smooth, Vascular; Necrosis; Rats; Rats, Sprague-Dawley; Swine; Thromboxane A2; Thromboxane-A Synthase

To investigate the protective effects and mechanism of action of aspirin on focal cerebral ischemia-reperfusion rats.. The right middle cerebral artery of the rat was occluded by inserting a thread through internal carotid artery for 2 h, and then reperfused for 24 h. Different doses of aspirin were intragastricly administrated at reperfusion 0 h and 6 h. The injured area of the brain and cerebral edema were estimated. The contents of prostacyclin (PGI2), thromboxane (TXA2), and endothelin (ET) in plasma were measured by 125I radioimmunoassay method. The content of nitric oxide (NO) in plasma was measured by the nitrate reductase method. The malondialdehyde (MDA) content in brain tissue was determined by the thiobarbituric acid method. The superoxide dismutase content (SOD) in brain tissue was assayed by the xanthine oxidase method. The content of adenosin 5'-triphosphate (ATP) in brain tissue was separated by capillary electrophoresis.. The injured area of the brain and the cerebral edema of occluded side were dramatically reduced after 6 and 60 mg.kg-1 doses of aspirin were administrated intragastricaly. The ratio of PGI2/TXA2 in plasma was increased by aspirin in a dose-dependent manner. In brain tissue of the occluded side, the MDA content was reduced from 9.0 +/- 0.75 to 6.48 +/- 0.74, and the ATP level was increased from 10.26 +/- 1.02 to 25.65 +/- 3.45 by the 60 mg.kg-1 dose of aspirin. No significant effect on SOD content was observed. In plasma, the NO content was significantly decreased from 24.76 +/- 1.88 to 8.17 +/- 0.79, and the ET level was increased from 254.85 +/- 21.14 to 278.43 +/- 16.79 by 6 mg.kg-1 dose of aspirin.. The neuroprotective effects of aspirin on focal cerebral ischemia-reperfusion rats might be attributed to its effects by increasing the ratio of PGI2 and TXA2, reducing lipid peroxides and improving the energy metabolism.

Topics: Animals; Aspirin; Brain Ischemia; Disease Models, Animal; Epoprostenol; Male; Malondialdehyde; Neuroprotective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase; Thromboxane A2

Oxygen radicals produced by activated neutrophils have been involved in brain injury during ischemia-reperfusion. Platelet-activating factor (PAF) is a candidate as one of the mediators of neutrophil activation during cerebral ischemia-reperfusion. Recent evidence indicates that PAF-induced neutrophil activation is mediated by thromboxane A2 (TXA2). To study the role of PAF and TXA2 in radical production during cerebral ischemia-reperfusion, we evaluated the effects of a PAF antagonist, Y-24180, and a TXA2 antagonist, S-1452, on radical formation in rats with 1 h middle cerebral artery (MCA) occlusion. In the present study, we employed a new electron spin resonance (ESR) method coupled with brain microdialysis. The method uses the endogenous ascorbyl radical (AR) concentration as a marker of oxygen radicals and requires no spin-trapping agents. In the vehicle controls, extracellular AR from the ischemic brain cortex decreased during MCA occlusion. Following reperfusion, AR significantly increased at 30 mm and 1 h, returned to near the basal levels at 2 h, and increased again at 24 h after reperfusion. In the rats treated with S-1452 or Y-24180, AR decreased during MCA occlusion to the same extent as in the vehicle control. However, pretreatment with Y-24180 or S-1452 significantly attenuated the increase in extracellular AR after reperfusion, while it exerted no effect on the changes in extracellular ascorbate or tissue pO2 throughout the experimental period. In conclusion, PAF and TXA2 might contribute to cerebral ischemia-reperfusion injury by increasing the generation of oxygen radicals.

Topics: Animals; Ascorbic Acid; Azepines; Brain; Brain Ischemia; Bridged Bicyclo Compounds; Dehydroascorbic Acid; Extracellular Space; Fatty Acids, Monounsaturated; Free Radicals; Male; Oxygen; Partial Pressure; Peroxidase; Platelet Activating Factor; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion; Thromboxane A2; Triazoles

Policosanol is a mixture of higher primary aliphatic alcohols, isolated from sugar cane wax, whose main component is octacosanol. Policosanol (25, 50 and 200 mg/kg) administered by the oral route not only significantly reduced serum thromboxane B2 (TXB2) levels but also, at 200 mg/kg significantly increased 6-keto-PGF1 alpha in Mongolian gerbils. Policosanol at 200 mg/kg significantly protected against cerebral ischemia induced by unilateral ligation of common carotid artery in Mongolian gerbils. In this experimental model, combined administration of ineffective doses of policosanol (25 mg/kg) and aspirin (ASA) (30 mg/kg) significantly protected animals indicating a synergism between them.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Brain Ischemia; Drug Synergism; Epoprostenol; Fatty Alcohols; Gerbillinae; Thromboxane A2; Thromboxane B2

The effects of CV-4151 on post-ischemic brain hypoperfusion and thromboxane (Tx)A2 production in a canine model of total global brain ischemia were studied. Complete cerebral ischemia for 5 min was produced in adult mongrel dogs by temporary ligation of the venae cavae and aorta. In the non-treated group, cerebral blood flow (CBF) increased during the first 20 to 30 min post-ischemia followed by a gradual decline and then stayed below preischemic level; CBF at 2 hr after the reperfusion was significantly reduced to ca 77% of the pre-ischemic level. Water content in the cerebral cortex at 2 hr after the reperfusion in the non-treated group was 78.15 +/- 0.21%, higher than the content in the control group, 76.70 +/- 0.07%. The concentration of TxB2 in the sagittal sinus was significantly increased at 30 min post ischemia. CV-4151 (1.0 mg/kg, i.v.) almost completely inhibited the post-ischemic hypoperfusion, significantly inhibited the increase in water content and almost completely inhibited the production of TxB2 in the post-ischemic period and increased the production of 6-keto PGF1 alpha. OKY-046 (10 mg/kg, i.v.) had no significant effects on both post-ischemic hypoperfusion and increase in water content in the cerebral cortex. We conclude that CV-4151 ameliorates post-ischemic cerebral hypoperfusion and that this improvement is associated with decreased sagittal sinus levels of TxB2.

Topics: Animals; Body Water; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Fatty Acids, Monounsaturated; Female; Male; Pyridines; Reperfusion Injury; Thromboxane A2; Thromboxane-A Synthase

Topics: Brain Ischemia; Female; Humans; Male; Sex Factors; Thromboxane A2; Thromboxane B2

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that is synthesized and released during reperfusion of ischaemic brain. We administered a TXA2 receptor antagonist, SQ29,548, and a thromboxane A synthase inhibitor, 1-benzylimidazole (1-BI), to rats subjected to 30 min of reversible forebrain ischaemia. Cerebral thromboxane B2 (TXB2), the stable metabolite of TXA2, measured after 60 min of reperfusion was 0.37 +/- 0.08 ng/mg brain protein in animals treated with SQ29,548/1-BI compared with 1.20 +/- 0.16 in ischaemic controls (p < 0.05). Cerebral pH determined by 31P magnetic resonance spectroscopy was higher in treated animals, 7.06 +/- 0.04, than in ischaemic controls, 6.5 +/- 0.01, after 20 min of reperfusion (p < or = 0.01). The significant elevation of cerebral pH in treated animals persisted at 30 (7.17 +/- 0.05 vs. 6.5 +/- 0.01; p < or = 0.01), 35 (7.17 +/- 0.05 vs. 6.44 +/- 0.04; p < or = 0.01), and 40 min of reperfusion (7.06 +/- 0.06 vs. 6.37 +/- 0.01; p < or = 0.05). We conclude that SQ29,548/1-BI reduces thromboxane levels and promotes resolution of tissue acidosis in ischaemic brain. The combination of a TXA2 receptor antagonist with a thromboxane A synthase inhibitor deserves further study as a potential treatment for acute cerebral infarction.

Topics: Acidosis; Animals; Brain Ischemia; Bridged Bicyclo Compounds, Heterocyclic; Drug Therapy, Combination; Fatty Acids, Unsaturated; Hydrazines; Hydrogen-Ion Concentration; Imidazoles; Magnetic Resonance Imaging; Male; Prosencephalon; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane-A Synthase

Topics: Adenosine Diphosphate; Blood Platelets; Brain Ischemia; Epoprostenol; Humans; Intracranial Embolism and Thrombosis; Platelet Aggregation; Platelet Function Tests; Serotonin; Thromboxane A2

The protective effect of thromboxane synthetase inhibitor, OKY-046, on brain ischemia was studied in spontaneously hypertensive rats. Cerebral ischemia was developed by bilateral carotid artery ligation (BCL) for 1 or 3 h and thereafter, circulation was restored for 15 min. OKY-046, 5 or 30 mg/kg, or saline as control was administered i.v. before BCL. Neither blood pressure nor blood gases were altered by OKY-046 or saline injection. During BCL, cerebral cortical blood flow was reduced to 25 and 15% of the resting value at 30 and 60 min, respectively, and these changes were not different among the groups. In rats with ischemia longer than 1 h, the blood flow was well preserved by OKY-046, 30 mg/kg, to 10-17% of the resting level, thus significantly higher than that (less than 5%) in non-treated rats. After 15 min recirculation, the supratentorial lactate level was lower and adenosine triphosphate (ATP) was higher in OKY-046-treated rats than in the saline-treated ischemic rats. Plasma thromboxane B2 was increased markedly in 1 h ischemic-reperfused rats without treatment and the increase was almost completely inhibited by OKY-046. In contrast, 6-keto-prostaglandin F1 alpha was increased 8.5-fold after ischemia and the increase was not affected by the treatment. OKY-046 seems to have an antiischemic effect on acutely induced cerebral ischemia. Selective inhibition of thromboxane A2 production and an inversely high level of prostaglandin I2 may be an important contribution to protection of the microcirculation during ischemia and preservation of ischemic cerebral metabolism.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Brain Chemistry; Brain Ischemia; Cerebrovascular Circulation; Epoprostenol; Female; Lactates; Methacrylates; Pyruvates; Radioimmunoassay; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase

To clarify the contribution of vasoconstrictor prostaglandins to the hypoperfusion state typically following total global cerebral ischemia, 14 mongrel dogs were subjected to 11 minutes of global cerebral ischemia. They were then randomly assigned to receive either no treatment or an intravenous bolus of the calcium channel blocker nimodipine, 10 micrograms/kg, 15 minutes after ischemia followed by a continuous infusion of nimodipine, 1.0 micrograms/kg/min. Thromboxane (Tx) A2 production, as measured by cerebral venous levels of TxB2 (the stable metabolite of TxA2) increased similarly in the two groups. In contrast to previous studies, mean postischemic cerebral blood flow did not increase sufficiently in the nimodipine-treated group to achieve statistical significance. These data suggest that the improved neurological outcome associated with nimodipine treatment following global cerebral ischemia does not relate to reduced levels of the prostaglandin precursor arachidonate.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Dogs; Nimodipine; Thromboxane A2

Three different levels of global forebrain ischemia were induced in rats and their plasma levels of Thromboxane B2 (TXB2) and 6 Keto PGF1 alpha were determined to investigate the relation between severity of ischemia and eicosanoid production. Ischemia stimulates the activity of cellular lipase whose actions cause deacylation of brain phospholipids and release of free fatty acids. Arachidonic acid (A.A.) is one of the predominant fatty acids which is liberated in brain after ischemia. A.A. is the primary substrate for the synthesis of prostaglandins (PGs), Thromboxane A2 (TXA2) and Prostacyclin (PGI2), which play an important role in regulation of platelet aggregation and vasotonus. Thromboxane is a potent platelet aggregator and vasoconstrictor. On the other hand, PGI2 has the opposite nature. Therefore it can be considered that PGs and moreover, the balance of TXA2 and PGI2 may have an intimate relation to the development of cerebral ischemia. Three different levels of ischemia were produced by bilateral carotid artery ligation (BLCL) using three kinds of rats with different blood pressure ranges, namely, SHRSP (Stroke-prone spontaneously hypertensive rats), SHRSR (Stroke-resistant spontaneously hypertensive rats) and WKY (Wistar kyoto rats). It is known that higher pressure groups suffer severe ischemia by BLCL procedure. Hypertensive rats (SHRSP, SHRSR) were originally produced from WKY. The experimental animals used were about 300 gr and 16 weeks old male rats. The plasma and brain TXB2 and 6 Keto-PGF1 alpha, stable metabolites of TXA2 and PGI2 were measured by radioimmunoassay. The chronological changes of brain and plasma PGs levels after ischemia using SHRSR were also investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Brain Chemistry; Brain Ischemia; Carotid Arteries; Cerebrovascular Circulation; Epoprostenol; Hypertension; Ligation; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2