prostaglandin-d2 and Subarachnoid-Hemorrhage

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

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

Free radicals and lipid peroxidation of membrane fatty acids are thought to play a role in the pathogenesis of arterial vasospasm and the physiopathologic patterns of neuronal damage after subarachnoid hemorrhage. We have evaluated the effects of treatment with either high-dose methylprednisolone every 8 hours or a single dose of U74006F on the temporal profile of ex vivo synthesis of four selected eicosanoids in brain slices after experimental induction of subarachnoid hemorrhage in rats. Prostaglandins D2 and E2, prostacyclin and leukotriene C4 levels were determined by radioimmunoassay after 1-hour incubation of the brain slices. The synthesis of prostaglandin D2 and 6-ketoprostaglandin F1 alpha at 48 hours after subarachnoid hemorrhage was significantly higher when compared to sham-operated animals (p = 0.01); prostaglandin E2 release was significantly enhanced at 6 hours after subarachnoid hemorrhage (p = 0.01). The release of the lipoxygenase metabolite was significantly enhanced at 1, 6, and 48 hours after subarachnoid hemorrhage induction. Both treatment regimens significantly reduced the ex vivo synthesis of prostaglandin D2, prostaglandin E2, and leukotriene C4 at 1, 6, and 48 hours after subarachnoid hemorrhage, whereas the effects on 6-ketoprostaglandin F1 alpha synthesis differed in the two treatment groups. U74006F enhanced the synthesis of prostacyclin metabolite in the early phase after subarachnoid hemorrhage, and high-dose methylprednisolone reduced the increasing synthesis at 48 hours. A strict comparison between the two treatments was not possible because of the different modalities of administration. However, these data suggest that the antioxidant effect of single-dose treatment with U74006F influenced the early and delayed effects on enzymatic lipid peroxidation, whereas the effects of methylprednisolone administration every 8 hours were more significant in the delayed phase.

Topics: Animals; Dinoprostone; Eicosanoids; Epoprostenol; Lipid Peroxides; Lipoxygenase; Male; Methylprednisolone; Pregnatrienes; Prostaglandin D2; Rats; Rats, Inbred Strains; Subarachnoid Hemorrhage

In the present study we have investigated the effects of high-dose methylprednisolone (MP) treatment on the 'ex vivo' release of four major eicosanoids in an experimental model of subarachnoid haemorrhage (SAH) with the aim of verifying: (a) the efficacy in reducing arachidonic acid metabolism enhancement; (b) whether high-dose methylprednisolone is effective on both the cyclooxygenase and lipoxygenase pathways; and (c) discussing the possible role of high-dose MP treatment in brain protection after SAH. Levels of prostaglandin D2 and E2, prostacyclin and also leukotriene C4 were determined by the radioimmunoassay technique after 1 h incubation of cerebral cortex samples of rats which had been subjected to experimental SAH procedure (injection of 0.3 ml of autologous arterial blood). The release of prostaglandin D2 at 48 h after SAH is significantly higher when compared to that of sham-operated animals (P less than 0.01); prostaglandin E2 release is significantly enhanced at 6 h after the SAH procedure (P less than 0.01); release of the lipoxygenase metabolite is significantly enhanced at 1, 6 and 48 h after SAH induction; MP significantly decreases the release of all eicosanoids, and values in treated animals do not differ from those of sham-operated animals. The results of the present study suggest that the global inhibitory effect of high-dose MP treatment on the 'ex vivo' release of eicosanoids after experimental SAH could be considered to be one of the neurochemical correlates for the reduced incidence and severity of arterial inflammatory response, which results in chronic vasospasm and supports the clinical evidence of MP efficacy in preventing or reducing the incidence of arterial vasospasm after aneurysmal rupture.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cerebral Cortex; Dinoprostone; Disease Models, Animal; Eicosanoids; In Vitro Techniques; Kinetics; Male; Prostaglandin D2; Rats; Rats, Inbred Strains; Reference Values; SRS-A; Subarachnoid Hemorrhage

The activation of lipid peroxidation and the enhancement of arachidonic acid metabolism have been demonstrated as indicators of brain damage after subarachnoid hemorrhage (SAH). Meanwhile, the final common pathway of neuronal damage seems to be related to the impaired homeostasis of Ca++. The present study evaluated the effect of the calcium-antagonist nicardipine on arachidonate metabolism after experimental induction of SAH. The ex vivo release of four eicosanoids (prostaglandin (PG)D2, PGE2, 6-keto-PGF1 alpha, and leukotriene (LT)C4) was measured at different intervals after SAH induction. Rats were separated into the following three groups: a sham-operated group, an SAH group (rats were injected with 0.3 ml autologous arterial blood), and an SAH-treated group (after SAH induction, rats were treated with nicardipine 1.2 mg/kg intraperitoneally). Nicardipine significantly decreased the ex vivo release of PGD2 at 48 hours after SAH (p less than 0.01). The release of PGE2 was significantly enhanced at 6 hours after SAH, while in the nicardipine-treated group PGE2 release is significantly reduced. Nicardipine also affects the lipoxygenase pathway, reducing the release of LTC4 at 1, 6, and 48 hours after SAH induction. The results of the present study show that nicardipine treatment exerts an inhibitory effect on both biochemical pathways of arachidonic acid metabolism; aside from vascular effects, nicardipine could exert a protective role against the release of arachidonate metabolites, which could play a significant role in the pathogenesis of brain damage after SAH.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Eicosanoids; Male; Nicardipine; Prostaglandin D2; Rats; Rats, Inbred Strains; SRS-A; Subarachnoid Hemorrhage

Arachidonic acid (AA) metabolites may play an important role in the pathogenesis of cerebral vasospasm which complicate subarachnoid hemorrhage. Authors have studied levels of 4 major AA metabolites in lumbar CSF samples and in CSF collected from perianeurismatic cisterns of 40 patients admitted with diagnosis of subarachnoid hemorrhage. Lumbar levels of AA metabolites are significantly higher in SAH patients than in control cases; moreover, cisternal CSF levels of PGD2, TxB2 and LTC4 are significantly higher than lumbar levels. Cisternal CSF levels (expressed in pg/ml +/- SEM) are in the "spasm" group: PGD2: 1129.62 +/- 146.33; 6-keto-PGF1 alpha: 214.2 +/- 19.96; TxB2: 4350.25 +/- 656.87; LTC4: 2582.19 +/- 381.83. In the "no spasm" group: PGD2 460.1 +/- 55.89; 6-keto-PGF1 alpha: 306.37 +/- 88.74; TxB2: 5752.5 +/- 899.25; LTC4: 812.92 +/- 142.06. Statistical analysis (paired t-test) shows values significantly higher for cisternal levels of PGD2 (P less than 0.005) and LTC4 (P less than 0.005) in patients presenting vasospasm. This suggests the importance of the subarachnoidal clot as a source of vasoactive compounds. Higher levels of leukotriene C4 in patients presenting vasospasm suggest a role for the compound in the genesis of local inflammatory processes and morphological changes of the arterial wall.

Topics: 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Humans; Intracranial Aneurysm; Prostaglandin D2; Prostaglandins D; SRS-A; Subarachnoid Hemorrhage; 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

Arachidonic acid metabolites are under investigation as possible vasoactive agents involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. Prostaglandins, as well as other vasoactive compounds, activate contractile proteins through utilization of extracellular bound Ca++ to the intracytoplasmic free fraction. Recently, calcium-antagonists, mainly Nimodipine, have been proposed for the prophylaxis and/or reversal of the ischemic damage caused by vasospasm. Nimodipine failed to reduce vasospasm incidence in a series of 30 patients admitted with diagnosis of subarachnoid hemorrhage from ruptured intracranial aneurysm. Nimodipine failed to reduce level of four arachidonate metabolites measured (prostaglandin D2, prostacyclin, thromboxane B2 and leukotriene C4) in lumbar and cisternal CSF. After subarachnoid hemorrhage there is a significant increase of CSF levels of arachidonate metabolites; in perianeurysmic cisterns level of prostaglandin D2, thromboxane B2 and leukotriene C4 are significantly higher than lumbar CSF levels. Moreover, cisternal CSF level of prostaglandin D2 and leukotriene C4 are significantly higher in patients with symptomatic vasospasm. Nimodipine did not significantly modify CFS level of arachidonate metabolites: this suggests that Nimodipine treatment, which definitely improves long-term results of patients for intracranial aneurysms, could exert its pharmacological action reducing Ca++ intake from the extracellular compartment and preventing a direct toxic effect of calcium, without a direct action against the release of vasoactive compounds.

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

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