6-ketoprostaglandin-f1-alpha and Ischemic-Attack--Transient

A wide literature exists about the pathogenesis of cerebral arterial spasm following subarachnoid haemorrhage: several compounds have been identified in human cerebrospinal fluid as possible vasoactive agents involved in the biochemical mechanism of vasospasm onset. Many experimental evidences exist for a major involvement of arachidonate metabolites. The present work represents a review of experimental data supporting the hypothesis of cerebral arterial spasm as a result of an imbalanced vascular regulatory mechanism involving arachidonate metabolites. The authors have also monitored, in 25 cases of aneurysmal subarachnoid haemorrhage, lumbar and cisternal CSF levels of prostacyclin and PGD2, as representative of vasodilating and, respectively, vasoconstrictor compounds. In all cases CSF arachidonate metabolite levels after SAH were significantly higher than in control cases. Ten patients presented with symptomatic vasospasm: lumbar CSF PGD2 levels show fluctuations with superimposed peaks related to the neurological deterioration due to vasospasm, while lumbar CSF prostacyclin concentration-trend suggest a decreasing synthesis. In 15 patients presenting without vasospasm, lumbar CSF concentration of arachidonate metabolites are in a 'steady-state'. These data confirm the existence of an imbalanced biochemical situation promoting vasospasm, markedly in cisterns near to the ruptured aneurysmal wall. The evaluation of cisternal CSF levels of arachidonate metabolites supports the hypothesis of the clotting phenomenon around the ruptured aneurysm as an important predictive pattern of vasospasm, as shown in CT findings.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Disease Models, Animal; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Prostaglandin D2; Prostaglandins D; Subarachnoid Hemorrhage

The effect of ozagrel, a selective thromboxane A(2) (TXA(2)) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO(2) after middle cerebral artery occlusion-reperfusion in cats. The level of TXB(2), a metabolite of TXA(2), in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF(1alpha), a metabolite of prostaglandin I(2) (PGI(2)), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI(2) improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA(2) and causing an increase in the PGI(2) level.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Chemistry; Cerebral Cortex; Enzyme Inhibitors; Epoprostenol; Imidazoles; Ischemic Attack, Transient; Male; Methacrylates; Mice; Motor Activity; Neuroprotective Agents; Oxygen Consumption; Psychomotor Performance; Rats; Rats, Inbred SHR; Reperfusion Injury; Specific Gravity; Thromboxane A2; Thromboxane-A Synthase

To study the effects of dl-3-n-butylphthalide (NBP) on the changes of thromboxane B2 (TXB2) and 6-keto-PGF1 alpha (6-keto-PGF1 alpha) contents in hippocampus, striatum, and cerebral cortex of rats subjected to focal cerebral ischemia followed by reperfusion.. Focal cerebral ischemia was induced by inserting a nylon suture into intracranial segment of internal carotid artery from external carotid artery and blockade of the origin of middle cerebral artery. For reperfusion, the suture was pulled out to restore the blood flow to the ischemic brain. Determination of TXB2 and 6-keto-PGF1 alpha was performed by RIA method.. Reperfusion following focal cerebral ischemia resulted in increases in TXB2 at 5 min and 6-keto-PGF1 alpha at 30 min and a decrease in the ratio of epoprostenol (PGI2)/thromboxane A2 (TXA2) (6-keto-PGF1 alpha/TXB2) at 5 min in hippocampus, striatum, and cerebral cortex. NBP 10 mg.kg-1 reduced the content of TXB2 without decreasing effect on 6-keto-PGF1 alpha. NBP 20 mg.kg-1 reduced both TXB2 and 6-keto-PGF1 alpha in lesser extent than aspirin (Asp, 20 mg.kg-1). NBP 20 or 10 mg.kg-1 elevated the ratio of PGI2/TXA2 after reperfusion, but Asp 20 mg.kg-1 did not increase the ratio except in striatum at 5 min after reperfusion.. NBP increases the ratio of PGI2/TXA2 which may have beneficial effects on the impaired microcirculation in postischemic brain tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Benzofurans; Brain; Ischemic Attack, Transient; Neuroprotective Agents; Rats; Reperfusion Injury; Thromboxane B2

Arachidonate metabolites have been implicated in the development of cerebral injury after ischemia. Particular importance has been placed on the balance of thromboxane A2 and prostaglandin I2 because of its regulative activity on platelet functions and arterial tone. The purpose of the present study was to shed light on the role of thromboxane A2 in postischemic brain injury.. We evaluated the effects of S-1452, a novel thromboxane A2 receptor antagonist, on brain edema, infarct areas, and survival rate in rats with middle cerebral artery occlusion. A transient middle cerebral artery occlusion model was produced by inserting a piece of silicon-coated nylon thread into the internal carotid artery.. The ratio of plasma thromboxane B2 to 6-keto-prostaglandin F1 alpha significantly rose at 0 hour (P < .05), 1 hour (P < .01), 3 hours (P < .05), and 12 hours (P < .05) and then nearly returned to the normal level at 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (5, 10, or 50 mg/kg PO) significantly attenuated the increase in postischemic water content in the cerebral cortex perfused by the anterior cerebral artery and the cerebral cortex perfused by the middle cerebral artery in a dose-dependent manner but slightly attenuated it in the caudate putamen 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (10 mg/kg PO) also significantly decreased the areas of infarction in the front parts of the cerebrum. The survival rate of animals after 2 hours of occlusion tended to be improved by treatment with S-1452 (10 mg.kg-1.d-1 PO), although there was no statistical significance.. Our results suggest that thromboxane A2 is closely related to postischemic brain injury in the early phase of recirculation and that S-1452 may have a protective effect on postischemic brain injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Brain; Bridged Bicyclo Compounds; Cerebral Infarction; Fatty Acids, Monounsaturated; Ischemic Attack, Transient; Male; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Survival Analysis; Thromboxane A2; Thromboxane B2; Time Factors

We measured hippocampal CA1 concentrations of PGD2, TxB2 and 6-keto-PGF1 alpha in 18 anesthetized rats with stereotaxically implanted microdialysis probes before, during and after 20 min of global cerebral ischemia. The insertion of the microdialysis probe did not appear to cause a continuous major disturbance of arachidonic acid (AA) metabolism because stable eicosanoid concentrations were obtained prior to ischemia. During reperfusion all three eicosanoids increased significantly reaching a peak after 30-60 min and then gradually declined to baseline levels over the next 2-3 h. The ratio of average peak concentrations for PGD2, TxB2 and 6-keto-PGF1 alpha were approximately 80:2:1, respectively. The results extend previous work by demonstrating the time course of eicosanoid release in a distinct brain region and confirm the role of PGD2 as the major PG metabolite in brain. We conclude that future studies employing microdialysis may be able to provide a more detailed understanding of the role of AA metabolites in ischemic brain.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Dialysis; Hippocampus; Ischemic Attack, Transient; Kinetics; Male; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Thromboxane B2

Using radioimmunoassay, fluorescence and transmittal++ electronmicroscopy, we studied the of prostaglandin(PG), lipid peroxidation(LPO) and ultrastructure. Fresh arterial blood (imaging acute spasm) produced basilar arterial spasm strongly(+ + +) and vacuole deterioration in vascular walls but there were no changes in 6-keto-PGF1 alpha and TXB2 and PGE2 and LPO. Incubated arterial blood (imaging chronic spasm) produced basilar arterial spasm markedly (+ + +) also. Vacuole deterioration in vascular walls either, and decreased the level of 6-keto-PGF1 alpha apparently (P < 0.01) and elevated the content of LPO significantly (P < 0.01) and there were no changes in the level of TXB2 and PGE alpha. This experiment suggests that the mechanism of acute spasm and chronic spasm is different.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Basilar Artery; Female; Ischemic Attack, Transient; Lipid Peroxides; Male; Rabbits; Subarachnoid Hemorrhage; Thromboxane B2

Authors addressed the question whether the byosynthesis and the release of specific eicosanoids may occur in human brain cortex, and if the qualitative pattern of arachidonic acid metabolism is similar to that observed in experimental SAH. Human brain samples from 18 patients operated on for anterior communicating artery aneurysm (5 unruptured aneurysms considered as control cases, 7 patients operated on between Days 1 and 4 after SAH and 6 patients operated on between Days 10 and 14) were studied for the ex vivo release of 4 selected eicosanoids (Prostaglandin D2, E2, 6-keto-PGF1a and Leukotriene C4). Levels of arachidonate metabolites were determined by radioimmunoassay technique. PGD2 release is significantly lower in cases operated on delayed phase if compared to both control cases (p less than 0.05) and patients operated on in the acute phase, while there is no significant difference between the release of PGD2 in control cases and patients operated on in the acute phase. Release of 6-keto-PGF1a is significantly higher in patients operated on in a delayed phase (p less than 0.03 vs patients operated on in the acute phase and p less than 0.05 versus control cases). The release of LTC4 is significantly enhanced (p less than 0.05) in cases operated on in the acute phase if compared with unruptured aneurysms. The release of PGE2 is significantly enhanced in patients operated on in the acute phase (p less than 0.05) if compared to patients with unruptured aneurysm.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cerebral Cortex; Culture Techniques; Dinoprostone; Eicosanoids; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Prostaglandin D2; SRS-A; Subarachnoid Hemorrhage

We investigated the hypothesis that cerebral prostanoid and peptidoleukotriene (LTs) (LTC4/D4/E4/F4) synthesis are increased during postischemic reperfusion of newborn pig brains. Prostanoids and LTs extracted from brain tissue were determined by RIA in sham-control piglets and at 1h, 3h, or 12h after a 20-min period of total cerebral ischemia. During reperfusion following ischemia, all regional brain tissue (cerebrum, brain stem and cerebellum) prostanoids (6-keto-PGF1 alpha, TXB2, PGE2 and PGF2 alpha) were increased at 1h compared with those in sham-control piglets. Only cerebral and brain stem 6-keto-PGF1 alpha and cerebral TXB2 remained elevated at 3h postischemia and all prostanoids returned to control levels by 12h postischemia. Brain tissue LTs were lower than prostanoids and were not altered 1, 3, or 12h following ischemia. These data indicate that 1) newborn pig brain tissue prostanoids are increased initially, and then returned to control levels at later stages of reperfusion following ischemia; 2) LTs are present in newborn pig brain tissue, but are not increased by ischemia/reperfusion injury and therefore probably do not play a significant role in cerebral ischemia-reperfusion injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Brain; Brain Stem; Cerebellum; Dinoprost; Dinoprostone; Female; Ischemic Attack, Transient; Leukotriene E4; Male; Prostaglandins; Reperfusion; SRS-A; Swine; Thromboxane B2

Arachidonic acid metabolites have been implicated in the development of cerebral edema following ischemia. To define the time course of metabolite production, subtemporal craniectomies were performed on 60 male Sprague-Dawley rats (350-400 g). Thirty rats underwent middle cerebral artery occlusion while 30 rats underwent craniectomy alone. Five rats in each of two groups (middle cerebral artery occlusion and sham) were sacrificed at 15 minutes, 1 hour, 4 hours, 1 day, 3 days, and 6 days. The cerebral hemispheres were removed and divided in the midsagittal plane. Each hemisphere was immediately frozen in isopentane cooled in dry ice and stored at -70 degrees C. Tissue prostaglandins E2 and 6-keto F1 alpha, and leukotrienes (LT) B4 and C4 were measured by radioimmunoassay. Prostaglandin E2 and 6-keto prostaglandin F1 alpha were significantly elevated at 15 minutes in the middle cerebral artery occlusion hemispheres (p less than 0.05). Prostaglandins were not significantly elevated after 15 minutes. LT B4 and C4 were never significantly elevated. Meclofenamate, a nonsteroidal anti-inflammatory agent, was administered to 21 additional rats. Seven controls underwent middle cerebral artery occlusion alone, 7 were given intraperitoneal meclofenamate (20 mg/kg) 30 minutes prior to middle cerebral artery occlusion, and 7 underwent middle cerebral artery occlusion followed immediately by intraperitoneal meclofenamate (20 mg/kg). The animals were sacrificed at 15 minutes and similarly studied. There was a significant reduction of prostaglandin E2 and 6-keto prostaglandin F1 alpha following pretreatment with meclofenamate (p less than 0.01 and p less than 0.05). In pretreated rats, leukotrienes were not affected by meclofenamate. Similarly, prostaglandins and leukotrienes did not change when meclofenamate was administered after middle cerebral artery occlusion. We conclude that cyclo-oxygenase metabolite production begins within 15 minutes of middle cerebral artery occlusion. Treatment with meclofenamate prior to middle cerebral artery occlusion significantly reduced cyclooxygenase metabolite production, suggesting a protective effect of meclofenamate against ischemia-induced elevations of vasoactive prostaglandins implicated in the development of cerebral edema. Lipoxygenase metabolite production was not affected by middle cerebral artery occlusion or pharmacological intervention.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebral Arteries; Constriction; Dinoprostone; Ischemic Attack, Transient; Leukotriene B4; Male; Meclofenamic Acid; ortho-Aminobenzoates; Rats; SRS-A; Time Factors

The correlation between protective effect of ginsenosides Rb + R0 and brain endogenously-derived prostacyclin synthesis, thromboxane A2 formation and lipid peroxidation were estimated in rats. Ginsenosides Rb + R0 100 mg/kg iv 30 min before 4-vessel occlusion elevated 6-keto-PGF1 alpha level, declined thromboxane B2 and brain edema formation, reduced the rise of lipid peroxides and suppressed the reduction in both creatine phosphokinase (CK) and superoxide dismutase (SOD) activities in brain tissue after 40-min ischemia followed by 1-h reperfusion. Furthermore, these improvements were partially abolished by pretreating with iv indomethacin. It is concluded that ginsenosides possess protective effect on cerebral ischemia-reperfusion injury of rats and ginsenosides Rb + R0 are the active principles. The underlying mechanism of protection is ascribed partially or mainly to the facilitated synthesis and release of prostacyclin, reduced formation of thromboxane A2 and inhibited generation of free radicals and subsequent lipid peroxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatine Kinase; Female; Ginsenosides; Ischemic Attack, Transient; Lipid Peroxidation; Male; Malondialdehyde; Panax; Plants, Medicinal; Rats; Rats, Inbred Strains; Reperfusion Injury; Saponins; Superoxide Dismutase; Thromboxane B2

The aim of our study was to investigate the changes of various biochemical parameters (concentrations of lactate, free arachidonate, cyclo- and lipoxygenase products) in rat brain after ischemia and reperfusion and the effects of pretreatment with the ganglioside derivative GM1-lactone on the same parameters. Ischemia was induced by reversible occlusion of common carotid arteries for 20 min, which included a final 5 min of respiration of 5% oxygen in nitrogen. Reperfusion was obtained by removing the occlusion. Pre-ischemic conditions were obtained on sham-operated animals. Animals were killed by microwave irradiation of their heads. Brain levels of lactate and of free arachidonate were markedly increased after ischemia and returned to normal values at 5 min of reperfusion. Levels of the cyclooxygenase metabolites prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were increased after ischemia, whereas levels of the lipoxygenase metabolite leukotriene C4 (LTC4) did not change. After reperfusion, a very marked increase of the cyclooxygenase products occurred but not of LTC4. Treatment with GM1-lactone prevented the elevation of cyclo- and lipoxygenase metabolites especially during reperfusion, with limited effects on lactate and free arachidonate levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Dinoprost; G(M1) Ganglioside; Ischemic Attack, Transient; Lactates; Lactic Acid; Lipoxygenase; Male; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (n = 8) or high-dose methylprednisolone (n = 8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha (a metabolite of prostacyclin), and thromboxane B2 (a metabolite of thromboxane A2) were measured in both treated and untreated (n = 7) dogs. In untreated dogs, the level of prostaglandin E2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F2 alpha levels were not significantly altered during the study. These data show that enhanced prostaglandin E2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Dinoprostone; Dogs; Ibuprofen; Ischemic Attack, Transient; Methylprednisolone; Subarachnoid Hemorrhage; Thromboxane B2

Previous studies have indicated that the regional distribution of the arachidonic acid metabolites around a focal ischemic lesion may be important in the pathogenesis of cerebral ischemia. To determine the functional significance of this regionalization, we examined the effect of imidazole (a thromboxane synthetase inhibitor) on the distribution of the vasoconstrictor thromboxane and the vasodilators prostacyclin and prostaglandin E2 (PGE2) and on the distribution of cerebral blood flow (CBF) around a focal ischemic lesion, middle cerebral artery (MCA) occlusion in the cat. The study was conducted in two phases. The first phase examined regional distribution of tissue arachidonic acid metabolites and the effect of imidazole treatment on that distribution. The second phase examined the effect of imidazole treatment on the distribution of blood flow about the focal ischemic lesion as well as on electrocortical function and edema production. MCA occlusion resulted in increased thromboxane, prostacyclin, and PGE2 levels in the ipsilateral hemisphere. These increases were greatest in the region of marginal ischemia and were present both 3 and 6 hours after occlusion. Imidazole pretreatment (50 mg/kg i.p.) significantly inhibited thromboxane production, but augmented production of prostacyclin and PGE2. In the blood flow studies, imidazole was without effect on regions of dense cerebral ischemia (CBF less than 20 ml/minute/100 g for more than 12 of 24 postocclusion hours). In regions of marginal ischemia (20 less than CBF less than 30 ml/minute/100 g for more than 12 of 24 postocclusion hours), imidazole pretreatment significantly increased blood flow in both gray and white matter compared with saline-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain; Brain Edema; Cats; Cerebrovascular Circulation; Dinoprostone; Evoked Potentials, Somatosensory; Imidazoles; Ischemic Attack, Transient; Prostaglandins E; Thromboxane B2; Thromboxane-A Synthase

To determine whether cerebral arteries in spasm have an altered capacity to synthesize the vasoactive substances prostacyclin and thromboxane A2, we measured levels of these arachidonic acid metabolites using a primate model of vasospasm. Twenty-four cynomolgus monkeys were assigned at random to one of three groups designated sham, clot, or clot-removal. All animals underwent base line cerebral angiography and bilateral dissection of the major cerebral arteries from the arachnoid. The clot and clot-removal groups had autologous hematomas placed around the vessels to simulate subarachnoid hemorrhages. The sham group had a similar volume of saline instilled into the subarachnoid space. Twenty-four hours later, the clot-removal group underwent a second craniotomy to remove the hematomas. Seven days after the initial operation, angiography was repeated on all animals. The animals were then killed, and the cerebral arteries were removed. Basal levels of prostacyclin and thromboxane in the cerebral vessels were measured after incubation in vitro by radioimmunoassay. No detectable leukotriene C4 release by these arteries was measurable using radioimmunoassay. Angiography revealed severe cerebral vasospasm in the clot group, but not in the clot-removal or sham groups. There were no statistical differences among the groups in thromboxane release, but prostacyclin levels were significantly lower in the clot group than in the clot-removal group (P less than 0.05). It thus seems that, if an imbalance in constrictor and dilator eicosanoids occurs in association with vasospasm, this is more likely to arise from a relative lack of the vasodilator component prostacyclin than from a surplus of the vasoconstrictor thromboxane.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebral Angiography; Cerebral Arteries; Epoprostenol; Female; Ischemic Attack, Transient; Macaca fascicularis; Osmolar Concentration; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Humans; Ischemic Attack, Transient; Prostaglandin D2; Prostaglandins D; SRS-A; Subarachnoid Hemorrhage; Thromboxane B2

Several naturally occurring compounds have been identified in human cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) as possible vasoactive agents involved in the biochemical mechanism of vasospasm. The authors have measured, in 30 patients admitted for SAH, CSF concentrations of two arachidonic acid metabolites. Prostacyclin and Prostaglandin D2, as representative of vasodilator and vasoconstrictor compounds. CSF samples were made available by lumbar punctures and intraoperative cisternal punctures. Nine patients presented with symptomatic vasospasm: lumbar CSF Prostaglandin D2 levels are significantly higher than in patients without vasospasm. The Cisternal Prostaglandin D2 level is significantly higher than the lumbar CSF concentration; CSF Prostacyclin levels do not significantly differ in the two groups of patients. These data suggest the presence of an imbalanced biochemical situation responsible for promoting vasospasm. The evaluation of cisternal levels of arachidonate metabolites support the hypothesis of the clotting phenomenon around the ruptured aneurysm wall as an important predictive pattern of vasospasm onset after SAH, as shown in computed tomography.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Epoprostenol; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Prognosis; Prostaglandin D2; Prostaglandins D; Risk; Rupture, Spontaneous; Subarachnoid Hemorrhage

Experimental investigations have suggested an important role of arachidonic acid metabolites in the genesis of cerebral vasospasm following subarachnoid hemorrhage. In this clinical study the cerebrospinal fluid (CSF) and serum levels of the two main arachidonic acid metabolites prostacyclin and thromboxane A2 are evaluated by measuring their stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) using radioimmunoassay methods during the pre- and postoperative course in patients after aneurysm rupture. Although the serum levels of both substances do not seem to be important for the clinical course of the patients, the CSF concentrations of 6-keto-PGF1 alpha and TXB2 provide important data. A close correlation between the initial TXB2 level of the individual patient and the amount of blood in the basal cisterns as detected by computed tomography scan can be demonstrated. The predictive value of this additional information for the occurrence of cerebral angiospasm is discussed. Comparing the CSF levels of both metabolites the slight preoperative elevation of 6-keto-PGF1 alpha is significantly surmounted by an extraordinary rise in TXB2 concentration. Postoperatively, after cleavage of the basal cisterns there is a decline in the CSF levels of both substances. The pre- and postoperative clinical course in comparison to the CSF levels of 6-keto-PGF1 alpha and TXB2 is demonstrated in four patients. A nearly normal course of TXB2 and 6-keto-PGF1 alpha seems to be associated with an uneventful clinical course, whereas a high TXB2 level--whether occurring preoperatively or, even more important, as a secondary postoperative rise--seems to be associated with ischemic complications and neurological deterioration. It is suggested that pre- and postoperative monitoring of CSF levels of 6-keto-PGF1 alpha and especially TXB2 may serve as a possible indicator for the detection of patients at risk of developing cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acids; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Risk; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Subarachnoid Hemorrhage; Thromboxane B2

Vasoactive arachidonic acid metabolites are postulated to play a role in the pathogenesis of cerebral ischemia. In order to characterize the local generation of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in transient ischemia with reperfusion, Mongolian gerbils were studied for regional cerebral blood flow (CBF), using the hydrogen clearance technique, and for cerebral levels of the thromboxane metabolite TXB2, and prostaglandins 6-keto-PGF1 alpha and PGE2, as well as the leukotriene LTB4. The gerbils were anesthetized with pentobarbital, and half of the animals were pretreated with the cyclooxygenase inhibitor indomethacin. All received 10 or 20 minutes of dense forebrain ischemia followed by reperfusion of 10 minutes, 50 minutes, or 100 minutes. A separate control group received no ischemic lesion. Regional CBF decreased significantly from 23.7 +/- 2.6 to 4.3 +/- 1.7 cc/100 gm/min during ischemia (p less than 0.01). Reperfusion resulted in initially normal flows (22.5 +/- 5.1 cc/100 gm/min) followed by a progressive hypoperfusion (11.3 +/- 2.7 cc/100 gm/min). All metabolites showed parallel significant (p less than 0.05) increases after transient ischemia and reperfusion compared to baseline levels (values (in pg/mg protein) were: TXB2 45.5 +/- 7.1 vs 23.3 +/- 3.6; 6-keto-PGF1 alpha 262.8 +/- 47.9 vs 175.8 +/- 26.8; PGE2 256.5 +/- 35.6 vs 112.5 +/- 11.2; and LTB4 37.8 +/- 4.6 vs 24.6 +/- 6). These levels were all significantly decreased (p less than 0.05) by pretreatment with indomethacin except for the leukotriene LTB4, which was increased. Transient cerebral ischemia results in a reperfusion abnormality and the local generation of cyclooxygenase products, which are reduced by pretreatment with indomethacin; however, cyclooxygenase inhibition may result in increased substrate availability for the lipoxygenase system. Studies of such an interaction may lead to new understandings of the pharmacological modification of detrimental vascular changes after transient cerebral ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Cerebrovascular Circulation; Gerbillinae; Ischemic Attack, Transient; Leukotriene B4; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Thromboxane A2

A large number of experimental data suggest a possible biochemical hypothesis for the trigger stimulus of cerebral vasospasm after subarachnoid hemorrhage (SAH). Among several classes of possible spasmogens, arachidonic acid metabolites may play a primary role. Authors have measured with radioimmunoassay technique (R.I.A.) the levels of four arachidonate metabolites (PGD2, TxB2, 6-keto-PGF1 alpha and i-LTC4) in lumbar and cisternal cerebrospinal fluid (CSF) of patients admitted with diagnosis of aneurysmal SAH. In all cases a significant activation of arachidonate metabolism is found, if compared to control cases. Patients with demonstrated vasospasm have significantly higher CSF levels of PGD2 and i-LTC4. Cisternal CSF levels of four metabolites are significantly higher than lumbar CSF levels. This suggests the correlation between subarachnoidal clot extension and the risk for vasospasm. Authors also present an experimental animal model of SAH, which is reliable from a pathological standpoint. This model could be therefore used in the study of neurochemical and neuropharmacological aspects of SAH.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Humans; Ischemic Attack, Transient; Prostaglandin D2; Prostaglandins; Prostaglandins D; Radioimmunoassay; Rats; Rats, Inbred Strains; SRS-A; Subarachnoid Hemorrhage

Imbalance between the two arachidonic acid metabolites, prostacyclin (PGI2) and thromboxane A2 (TXA2), is thought to be at least in part responsible for the development of cerebral vasospasm following aneurysm rupture. In 12 patients with subarachnoid hemorrhage the pre- and postoperative serum and CSF levels of PGI2 and TXA2 were measured as a function of their stable hydrolysis products, 6-Keto-PGF1 alpha (PGI2) and thromboxane B2 (TXA2), with a highly specific radioimmunoassay. Serum levels of both metabolites were elevated in half of the patients, but no correlation to the clinical course could be found. However, TXB2 concentration in the CSF was significantly increased preoperatively with close correlation to the amount of intracisternal blood, as detected by CT scan. Furthermore, it could be demonstrated that the postoperative course of the TXB2 concentrations in the CSF reflects the clinical course in such a way that a characteristic secondary rise of TXB2, concentration postoperatively is closely related to the occurrence of cerebral vasospasm and clinical deterioration. The conclusion is drawn that measurement of arachidonic acid metabolites in the CSF may provide important information concerning the pathophysiological events following subarachnoid hemorrhage, especially with regard to incipient cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Carotid Artery Diseases; Carotid Artery, Internal; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane B2

Experimental and clinical observations suggest the importance of arachidonate metabolites in the genesis of symptomatic cerebral vasospasm after subarachnoid hemorrhage. Prostacyclin (PG12) has a well demonstrated vasodilator action. The authors monitored CSF prostacyclin concentration in 12 consecutive cases of subarachnoid hemorrhage with the purpose of correlating the prostacyclin concentration trend with the clinical course and the risk for vasospasm. In three cases patients presented with clinical and radiological signs of vasospasm. CSF prostacyclin concentration showed a typical decreasing trend, which amounted to a minor form of protection from vasospastic agents. The nine cases which did not develop vasospasm demonstrated no significant changes in the prostacyclin CSF concentration trend. The authors also presented four cases in which cisternal CSF samples were available. In one case of developing vasospasm, the cisternal prostacyclin concentration was seven times lower than the highest lumbar CSF concentration. In three cases without evidence of vasospasm cisternal CSF demonstrated a balanced biochemical situation and a minor risk of vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Subarachnoid Hemorrhage

Effects of OKY-046, a selective inhibitor of thromboxane (TX)A2 synthetase and a platelet aggregation inhibitor, on in vitro and in vivo models of cerebral vasospasm were studied. The contraction of the isolated rabbit basilar artery by an exposure to 1.0 ml of whole rabbit blood plus 0.05 or 0.1 units/ml of thrombin was diminished by the treatment with 10(-4) M of OKY-046 and/or 10(-6) M of cinanserin. When the whole blood of rabbits treated intravenously with 1 mg/kg/min of OKY-046 was used, the contraction of the basilar artery was decreased to about half of the control contraction. Angiographically recognized cerebral vasospasm in vivo, by a transorbital injection of 5.0 to 7.0 ml of autologous arterial blood into the cisterna magna of dogs, was suppressed by 0.05 and 0.5 microgram of OKY-046. Moreover, the decrease in the regional cerebral blood flow in autologous blood infused-dogs was inhibited by 0.5 microgram of OKY-046. The increase in TXB2 in the cerebrospinal fluid of dogs was significantly inhibited, and the level of 6-keto-PGF1 alpha was slightly increased by the treatment of OKY-046. The ratio of 6-keto-PGF1 alpha/TXB2 was increased from 1.5 to 5.2 in OKY-046-treated dogs. No effect on the basal tone and response to vasoactive agonists such as norepinephrine, KCl and PGE1 was observed in the isolated spiral thoracic aorta of guinea pigs or rabbits. Taken together with our previous findings, we conclude that the inhibition of cerebral vasospasm in the in vitro and in vivo models by the treatment of OKY-046 might be due to an inhibition of platelet aggregation, an inhibition of TXA2 generation and an increase in the ratio of PGl2/TXA2.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Aorta; Basilar Artery; Brain; In Vitro Techniques; Ischemic Attack, Transient; Methacrylates; Rabbits; Regional Blood Flow; Thromboxane B2

Two representative cases of subarachnoid hemorrhage in which prostaglandin D2 (PGD2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolite of prostacyclin (PGI2), were monitored with serial lumbar punctures and detected in cisternal CSF during operations for aneurysm, are reported. In the case with demonstrated arterial vasospasm, prostaglandin D2 has a concentration trend with characteristic peak related to vasospasm; the synthesis of prostacyclin appears inhibited after the hemorrhage. In the patient without radiologic evidence of vasospasm, arachidonate metabolite concentration trend appears in a steady-state. Cisternal prostaglandin D2 concentration in the patient with demonstrated vasospasm is two times the highest lumbar CSF concentration, while 6-keto-prostaglandin F1 alpha concentration is very low. This suggests the role of the clotting phenomenon and likely confirms the importance of arachidonate metabolites in the genesis of cerebral arterial spasm following subarachnoid hemorrhage.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Cerebral Angiography; Cisterna Magna; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Lumbosacral Region; Prostaglandin D2; Prostaglandins D; Rupture, Spontaneous; Spinal Cord; Subarachnoid Hemorrhage