prostaglandin-d2 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

We examined the role of cyclooxygenase-2 in the development of ischemic tolerance induced by cortical spreading depression against transient, focal brain ischemia. Cortical spreading depression was continuously induced for 2 h with topical KCl (13+/-1 depolarizations/2 h) in male Wistar rats. At 1, 2, 3, 4, and 5 days following recovery, the middle cerebral artery was transiently occluded for 120 min. Four days later, the animals were killed and infarct volume was determined. Additionally, cyclooxygenase-2 levels in the cerebral cortex and 15 deoxy-Delta(12, 14) PGJ2 levels in cerebrospinal fluid were determined at these times with Western blotting and immunoassay, respectively. Infarct volume was reduced compared with non-cortical spreading depression control animals (274.3+/-15.3 mm3) when cortical spreading depression was performed 3 and 4 days before middle cerebral artery occlusion (163.9+/-14.2 mm3, 154.9+/-14.2 mm3) but not at 1, 2 and 5 days (280.4+/-17.3 mm3, 276.3+/-16.9 mm3 and 268.5+/-17.3 mm3). Cyclooxygenase-2 levels increased most dramatically starting at 2 days, peaked at 3 days, and started to return toward baseline at 4 days after cortical spreading depression. 15 Deoxy-Delta(12, 14) PGJ2 levels increased from 134.7+/-83 pg/ml at baseline to 718+/-98 pg/ml at 3 days. Administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide (10 mg/kg, i.v.), a selective cyclooxygenase-2 inhibitor, at 1 h prior to middle cerebral artery occlusion in cortical spreading depression preconditioned animals did not affect infarct volume (162.6+/-62.1 mm3). However, administration of N-[2-cyclohexyloxy-4-nitrophenyl] methanesulphonamide given three times prior to middle cerebral artery occlusion prevented the reduced infarct volume induced by cortical spreading depression preconditioning (272.9+/-63.2 mm3). Administration of L-nitro-arginine methyl ester (4 mg/kg, i.v.) prior to cortical spreading depression blocked increases in cyclooxygenase-2 normally seen at 3 and 4 days. We conclude that NO-mediated cyclooxygenase-2 upregulation by cortical spreading depression protects the brain against ischemic damage.

Topics: Animals; Cerebral Cortex; Cerebral Infarction; Cortical Spreading Depression; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytoprotection; Disease Models, Animal; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Ischemic Preconditioning; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Potassium Chloride; Prostaglandin D2; Rats; Rats, Wistar; Up-Regulation

Inducible cyclooxygenase (COX-2) catalyzes the first step in prostanoid biosynthesis and is considered a proinflammatory enzyme. COX-2 and type 1 inducible PGE synthase (mPGES-1) have a role in metalloproteinase (MMP) release leading to plaque rupture. In contrast, lipocalin-type PGD synthase (L-PGDS) has been shown to exert antiinflammatory actions. Thus, in this study we investigated whether a shift from a PGDS-oriented to a PGES-oriented profile in arachidonate metabolism leads to inflammatory activation in rupture-prone plaque macrophages.. Atherosclerotic plaques were obtained from 60 patients who underwent carotid endarterectomy, symptomatic (n=30) and asymptomatic (n=30) according to evidence of recent transient ischemic attack or stroke. Plaques were analyzed for COX-2, mPGES-1, L-PGDS, PPARgamma, IkappaBalpha, NF-kappaB, and MMP-9 by immunocytochemistry, Western blot, reverse-transcriptase polymerase chain reaction, enzyme immunoassay, and zymography. Prostaglandin E2 (PGE2) pathway was significantly prevalent in symptomatic plaques, whereas PGD2 pathway was overexpressed in asymptomatic ones, associated with NF-kappaB inactivation and MMP-9 suppression. In vitro COX-2 inhibition in monocytes was associated with reduced MMP-9 release only when PGD2 pathway overcame PGE2 pathway.. These results suggest that COX-2 may have proinflammatory and antiinflammatory properties as a function of expression of downstream PGH2 isomerases, and that the switch from L-PGDS to mPGES-1 in plaque macrophages is associated with cerebral ischemic syndromes, possibly through MMP-induced plaque rupture.

Topics: Arachidonic Acid; Carotid Artery Diseases; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Humans; I-kappa B Proteins; Inflammation; Intramolecular Oxidoreductases; Ischemic Attack, Transient; Isoenzymes; Lipocalins; Macrophages; Matrix Metalloproteinase 9; Membrane Proteins; NF-kappa B; NF-KappaB Inhibitor alpha; PPAR gamma; Prostaglandin D2; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases; Stroke

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

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

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

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

Experimental and clinical studies indicate that cerebral vasospasm following subarachnoid hemorrhage (SAH) may be caused by changed biochemical properties of the endothelium and vascular smooth muscle cell exposed to vasoactive substances synthetized by cerebral arteries and released in clotted blood. Many compounds have been identified in CSF from SAH patients: Thromboxanes A2 and B2, Prostaglandins F2 alpha, E2 and D2 are the major prostanoids incriminated in the causation of cerebral arterial spasm. We have monitored the CSF PGD2 concentrations with serial lumbar punctures at different intervals from the hemorrhage in 16 patients admitted for SAH: PGD2 was measured with radioimmunoassay as its 9-methoxy derivative. The lumbar CSF PGD2 concentration ranges from 0.11 to 1.53 ng/ml. In 7 cases vasospasm was angiographically demonstrated. 9 patients presented no clinical or radiological evidence of vasospasm. In 5 cases cisternal CSF samples were available at the operation by cisternal punctures. There was no correlation between CSF PGD2 concentration and clinical course. In the 7 cases with evidence of vasospasm a significant increase of CSF PGD2 corresponded to neurological deterioration. In all 9 cases without evidence of vasospasm CSF PGD2 concentration trend was in a steady-state. The cisternal CSF PGD2 concentration was higher than lumbar CSF concentration in cases with arterial spasm. This suggests the importance of the clotting phenomenon in vasospasm onset after SAH. PGD2 is one of the most important spasmogens in clotted blood. Although its role in the genesis of vasospasm onset remains to be defined, its vasospastic action, in addition to that of other analogous compounds, seems to be relevant.

Topics: Humans; Ischemic Attack, Transient; Lumbosacral Region; Monitoring, Physiologic; Prostaglandin D2; Prostaglandins D; Radioimmunoassay; Subarachnoid Hemorrhage

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