Eicosanoids in third ventricular cerebrospinal fluid of fetal and newborn sheep.

A method to serially sample cerebrospinal fluid (CSF) from the third ventricle of chronically catheterized fetal and newborn sheep was developed. Either sampling cannulas of preset lengths ("fixed-probe" technique) or a single cannula that could be positioned at the desired depth ("roving-probe" technique) was used. The roving probe proved superior because free CSF flow was obtained in seven of ten animals after surgery compared with two of nine animals implanted with a fixed probe. CSF (5 animals) and plasma (7 animals) was collected serially from 2 wk before to 2 wk after birth, including the time around labor. Prostaglandin E2 (PGE2) levels (means +/- SE) were significantly higher in CSF (366 +/- 120 pg/ml; n = 5) and plasma (520 +/- 69 pg/ml; n = 7) before the day of delivery than in the same animals after birth. During labor, CSF and plasma PGE2 levels increased significantly to 1,428 +/- 643 pg/ml in CSF and to 2,015 +/- 414 pg/ml in plasma. However, by 1 h after birth, PGE2 had fallen to 366 +/- 165 pg/ml in CSF and to 338 +/- 106 pg/ml in plasma; levels similar to those observed in the fetus before labor. PGE2 continued to decrease precipitously and, at 24 h of age, levels were significantly less than those observed in the fetus. PGE2 levels were near the limit of detection of the assay in CSF (< 5 pg/ml) and were 49 +/- 10 pg/ml in plasma. In contrast, CSF thromboxane B2 (n = 2) and total peptidoleukotriene content (n = 4) showed little change during labor or after birth.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients.

The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.

Effect of leukotriene antagonist on experimental delayed cerebral vasospasm.

Experimental delayed cerebral vasospasm was produced in 16 adult mongrel dogs by the "two-hemorrhage" method of intracisternal injections of autologous arterial blood. Group 1 was a control group. Group 2 was a treatment group that received an intravenous injection of ONO-1078, a novel potent leukotriene antagonist, once a day for 7 days just after the first cisternal injection of the blood. Angiography was performed on Days 0 and 7, and the cerebrospinal fluid levels of leukotriene C4 (LTC4) were measured on Days 0, 3, and 7. The cisternal levels of LTC4 increased after subarachnoid hemorrhage in both groups. But the cerebrospinal fluid levels of LTC4 in the treatment group were significantly lower than those in the control group (P less than 0.05). The angiographic vasospasm after subarachnoid hemorrhage was partially prevented with the treatment of intravenous injections of ONO-1078 (P less than 0.001). These results suggest that LTC4 may play a role in the pathogenesis of delayed cerebral vasospasm, directly or indirectly, and ONO-1078 may have a therapeutic effect on the prevention of the development of delayed cerebral vasospasm.

Mediator release in cerebrospinal fluid of human immunodeficiency virus-positive patients with central nervous system involvement.

In this study we evaluated the release of some mediators of inflammatory reactions such as histamine (H), leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in the cerebrospinal fluid (CSF) of 15 patients with acquired immunodeficiency syndrome (AIDS), eight with opportunistic infections of the central nervous system (CNS) and seven without HIV-related neurological pathology, and of 25 HIV-negative control subjects with other neurological diseases. The cerebrospinal LTB4 level was increased in all the AIDS patients (mean 348 pg/ml); the control group revealed normal levels of LTB4 in the CSF (mean 63.2 pg/ml). The PGD2 level in the HIV-positive (mean 264 pg/ml) patients was higher than of the control subjects (mean 50 pg/ml), while low LTC4 levels were found both in the HIV-positive and control groups. We did not find any significant concentration of H in the CSF of either the HIV-positive or the control subjects. These findings may be due to the presence of chronic HIV infection or to the opportunistic infections of the CNS that so often occur in the latest stages of the disease.

Leukotriene C4 and prostaglandin E2 activities in the serum and cerebrospinal fluid during acute cerebral ischemia.

Lipoxygenase pathway products of arachidonic acid (AA) metabolism (known as leukotrienes, LTs) are produced in the brain during pathologic conditions such as ischemia, hemorrhage, trauma, and seizure in which the release of AA is sustained by the activation of local phospholipases. The most common type of LT in the central nervous system is an LTC4 which is a highly potent vasoconstrictor leading to increase in vascular permeability. In this study, we compared the serum (S) and cerebrospinal fluid (CSF) prostaglandin E2 (PGE2) and LTC4 levels in 13 consecutively admitted patients with acute cerebral ischemia aged 55-80 years with 10 age-matched controls. Patients with previous glucocorticosteroid and antiinflammatory drug usage were not included in the study. S and CSF samples were drawn during the first 72 h of the attack, and samples were evaluated by bioassay. There was no significant difference in S PGE2 and LTC4 values, whereas a significant difference was observed between CSF PGE2 and LTC4 values as compared with the control group. The high levels of CSF PGE2 and LTC4-like activity in acute cerebral ischemia may indicate that these mediators have a role to play in cerebral edema. The CSF PGE2/LTC4 ratio was also found to be reduced in the ischemic group implying higher LTC4 synthesis than PGE2 synthesis. In the light of these findings, we suggest that use of a selective antagonist of LTs may be helpful in reducing the ischemic penumbra during acute cerebral ischemia by controlling the vasogenic edema.

[Leukotrienes and neurological diseases]. / Leukotrienler ve nörolojik hastaliklar.

Assessment of Leukotriene C4 (LTC4) activity in the serum and cerebrospinal fluid (CSF) specimens of patients with multiple sclerosis (MS), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Myasthenia gravis (MG), Behçet's disease and neuro-Behçet, as well as in normal controls were carried out in order to determine its role in the pathogenesis of neurologic disorders. LTC4 levels were found to be elevated in MS and Behçet patient in comparison with controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the pathogenesis of these disorders.

CSF leukotriene C4 following subarachnoid hemorrhage.

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.

A study on cisternal CSF levels of arachidonic acid metabolites after aneurysmal 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.

Eicosanoids in human ventricular cerebrospinal fluid following severe brain injury.

Recent evidence has shown that a variety of prostaglandins and leukotrienes can be produced in brain tissue after injury in animals. It has also been speculated that increases in brain prostaglandins occur in humans following injury. Ventricular cerebrospinal fluid (CSF) samples have been obtained from children with static lesions (controls) as well as children with acute brain injury and eicosanoids measured by immunologic techniques. Metabolites of prostacyclin (6-keto-PGF1 a) and thromboxane A2 (thromboxane B2) were the major eicosanoids found in CSF, and levels of these compounds were increased 3-10 times in acutely injured patients. Prostaglandin E2 was also found in lower amounts, although in one case its level was very high. Prostaglandin D2 was also present, but in low amounts. No leukotrienes were found in CSF samples that were purified by HPLC prior to immunoassay. Elevated levels of hydroxyeicosatetraenoic acids (HETEs) were observed in those samples stored frozen, but these metabolites were most probably due to autooxidation of arachidonic acid in CSF. Arachidonic acid concentration in CSF was typically found to be in the range of 10-200 ng/ml, but was found to be 5-10 fold higher in one severely injured patient. Thus, elevated free arachidonic acid and various oxygenated metabolites were observed in CSF following brain injury.

Effect of nimodipine on arachidonic acid metabolites after 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.

[Cerebral vasospasm. Clinical and experimental aspects]. / Il vasospasmo cerebrale. Aspetti clinico-sperimentali.

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.

Leukotriene C4 transport and metabolism in the central nervous system.

The transport and metabolism of radiolabeled leukotriene (LT) C4 in the CNS were investigated after intraventricular injection. Under thiopental (Pentothal) anesthesia, New Zealand white rabbits were injected intracerebroventricularly with 0.2 ml of artificial CSF containing 2.5 microCi of [3H]LTC4 (36 Ci/mmol), 0.3 microCi of [14C]mannitol, and, in some cases, 0.9 mg of probenecid, 1.8 mg of cysteine, 1.4 micrograms of unlabeled LTC4, or 2 mg of tolazoline HCl. After 2 h, the conscious rabbits were killed, and the quantity and nature of the 3H and 14C were determined in CSF, choroid plexus, and brain. The [3H]LTC4 recovered in CSF and brain was not extensively metabolized, as greater than 70% of the 3H remained [3H]LTC4, although some spontaneous conversion to 11-trans-[3H]LTC4 occurred. Oxidized forms of [3H]LTC4, [3H]LTD4, and [3H]LTE4 did not exceed 18% in CSF and brain. After intraventricular injection of [3H]LTC4, 3H was transferred from the CSF to blood by a probenecid-sensitive, but tolazoline-insensitive, transport system in the CNS much more rapidly than mannitol. Cysteine decreased the retention of [3H]LTC4 in brain. These results are consistent with previous in vitro observations that [3H]LTC4 is transferred from CSF into blood by an efficient transport system for LTC4 in choroid plexus.

Formation of lipoxygenase and cyclooxygenase metabolites of arachidonic acid by brain tissue.

Rat brain slices released spontaneously and after challenge with A23187 LTC4-like radioimmunoactivity. Total cat brain ischemia followed by short postischemic reperfusion period resulted in the increased release of lipid peroxides and PGE2 but not in LTC4-like substance by brain slices. In lumbar cerebrospinal fluid of patients with completed stroke presence of LTC4-like material was observed.