Additive effect of cyclooxygenase and nitric oxide synthase blockade on the cerebrocortical microcirculation.

The contribution of vasodilator cyclooxygenase (COX) metabolites to the maintenance of the cerebrocortical blood flow (CBF) has been studied under physiological conditions and in nitric oxide (NO) deficiency. Inhibition of COX decreased resting CBF without changing arterial blood pressure. NO synthase blockade resulted in hypertension and CBF reduction as well as in enhanced cerebral prostacyclin and prostaglandin E2 production. Despite the increased vasodilator prostanoid release in the absence of NO, the CBF-decreasing effect of COX blockade failed to increase. Therefore, the COX pathway seems to play a similar role under physiological and NO-deficient conditions in the maintenance of the resting CBF.

Vasodilatory prostaglandins in perinatal hypoxic brain damage.

Prostaglandin (PGE2 and PGI2) synthesis was determined in the cerebrospinal fluid (CSF) and serum of 19 hypoxic neonates at the age of 5-96 hours by using Enzyme Linked Immunosorbent Assay (ELISA) method. Control group consisted of 8 children of the same age whose samples were taken due to initial suspicion of neonatal meningitis. The prostaglandin concentrations in CSF were correlated with initial hypoxic-ischemic encephalopathy (HIE) stage and neurological findings of patients at the age of 12 months. The values of PGE2 and PGI2 in the CSF of children with perinatal hypoxia (PNH) were significantly higher than in the children from the control group. The values of PGI2 in serum were significantly higher than in "CSF" of patients with PNH. Although average values of PGE2 and PGI2 in the liquor were higher in children with advanced stage of HIE, the differences between different stages were not statistically significant. We did not find any significant correlation between average concentrations ofprostaglandins and neurological findings of the 12-month-old children.

Clinical implication of the changes of cAMP, TXA2 and PGI2 in CSF of asphyxiated newborns.

To evaluate the changes of 3', 5'-cyclic adenosine monophosphate (cAMP), thromboxane A2(TXA2) and prostacyclin (PGI2) in cerebrospinal fluid (CSF) in the asphyxiated newborn and explore their roles in hypoxic-ischemic brain damage (HIBD). Thirty-six full term newborns were divided into 3 groups, including 12 with moderate-severe hypoxic-ischaemic encephalopathy (HIE), 13 with mild HIE, 11 without HIE (control group). The levels of cAMP, TXB2 (TXA2 metabolite) and 6-keto-PGF1 alpha (PGI2 metabolite) in CSF and plasma were measured 36-72 h after birth by RIA, and the concentrations were expressed as nM/L (cAMP), ng/L(TXB2 and 6-keto-PGF1 alpha). The infants were followed-up at 6 and 12 month of age and Mental Development Index (MDI) and Psychomotor Development Index (PDI) were measured using Bayley Scales of Infant Development (BSID). The CSF cAMP level in moderate-severe HIE group was 8.60 +/- 2.40, significantly lower than that of the mild HIE group (14.83 +/- 2.84) and the control group (24.43 +/- 2.39) (for both P < 0.01). The levels of TXB2 and 6-keto-PGF1 alpha in CFS in the moderate-severe HIE group (206.06 +/- 29.74, 168.47 +/- 23.02, respectively) were significantly higher than in the mild HIE group (83.37 +/- 28.57, 131.42 +/- 16.57, respectively, P < 0.01) and the control group (41.77 +/- 21.58, 86.23 +/- 13.05, respectively, P < 0.01). The level changes of cAMP, TXB2 and 6-keto-PGF1 alpha in plasma in all groups were similar to those in CSF, but no significant difference was found between mild HIE group and the control group (P > 0.05). The follow-up results showed that MDI and PDI of the moderate-severe HIE group were the lowest (84.79 +/- 13.34, 83.50 +/- 13.28, respectively), followed by mild HIE group (102.19 +/- 7.02, 99.94 +/- 9.08, respectively), with the control group being the highest (116.63 +/- 12.08, 116.69 +/- 10.87, respectively). Univariate analysis showed some significant difference (the moderate-severe HIE group vs. the mild HIE group or the control group, P < 0.01; the mild HIE group vs. the control group P < 0.05). The results suggested that the concentration of cAMP, TXA2 and T/K ratio in CSF after neonatal asphyxia might be sensitive markers in evaluating the severity of brain damage in early stage and predicting the future outcome.

Cerebrospinal fluid prostaglandins, interleukin 1 beta, and tumor necrosis factor in bacterial meningitis. Clinical and laboratory correlations in placebo-treated and dexamethasone-treated patients.

Prostaglandins (PGs), interleukin 1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) are likely mediators of local inflammatory reactions. We measured PGE2, PGI2, IL-1 beta, and TNF concentrations in paired cerebrospinal fluid (CSF) samples (on admission, CSF1, and 18 to 30 hours later, CSF2) from 80 infants and children with bacterial meningitis. Forty patients received dexamethasone sodium (0.6 mg/kg per day in four intravenous doses) and 40 received an intravenous saline placebo. In CSF1, PGE2, PGI2, IL-1 beta, and TNF were detected in 90%, 56%, 98%, and 71% of specimens with mean (+/- SEM) concentrations of 462 +/- 65, 377 +/- 62, 1266 +/- 242, and 799 +/- 227 pg/mL, respectively. Concentrations of PGE2 correlated significantly with PGI2, IL-1 beta, TNF, and lactate and inversely correlated with glucose concentrations in the first CSF specimens. The PGE2, PGI2, IL-1 beta, and TNF were still detected in 40%, 18%, 97%, and 60%, respectively, of second CSF specimens obtained from placebo-treated patients. Compared with patients who had detectable PGI2 or TNF alpha concentrations in CSF2 specimens, those placebo-treated patients with no detectable PGI2 or TNF alpha activity in CSF2 had a lower incidence of neurological sequelae. Dexamethasone-treated patients had significantly lower PGE2, IL-1 beta, and lactate concentrations and higher glucose concentrations in CSF 18 to 30 hours later, shorter duration of fever, and a lower incidence of neurological sequelae than did placebo-treated patients.

Postasphyxial increases in prostanoids in cerebrospinal fluid of piglets.

The dilator stimuli that contribute to postasphyxial increases in cerebral blood flow in the neonate are unclear. To assess the possible role of cyclooxygenase products in these responses, we measured pial arteriolar diameter in six piglets and determined levels of prostaglandin (PG) E2 and 6-keto-PG F1 alpha (hydrolysis product of PGI2) in cerebrospinal fluid (CSF) bathing the parietal cortex during control conditions, after 4-10 min of complete respiratory arrest (asphyxia), and after 5-12 min of reventilation. Pial arterioles are important resistance vessels in the cerebral circulation. Baseline pial arteriolar diameter was 220 +/- 40 micron (mean +/- SEM) and increased to a maximum of 252 +/- 49 and 267 +/- 56 micron after asphyxia and reventilation, respectively. During control conditions, CSF PGE2 (n = 6) and 6-keto-PGF1 alpha (n = 4) levels were 1947 +/- 310 and 794 +/- 147 pg/ml, respectively. During asphyxia, CSF levels of PGE2 did not increase, whereas 6-keto-PGF1 alpha increased modestly. During reventilation, CSF PGE2 increased to 3576 +/- 499 pg/ml, and 6-keto-PGF1 alpha increased to 2846 +/- 123 pg/ml. In other experiments, we determined that these CSF levels of PGE2 and PGI2 (as 6-keto-PGF1 alpha) were within the vasodilator range for pial arterioles. We conclude that postasphyxial increases in pial arteriolar diameter are associated with a rise in CSF levels of dilator prostanoids.

Cisternal and lumbar CSF levels of arachidonate metabolites after subarachnoid haemorrhage: an assessment of the biochemical hypothesis of vasospasm.

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.

Arachidonate metabolites and vasospasm after subarachnoid haemorrhage.

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.

Prostacyclin and vasospasm in subarachnoid hemorrhage from ruptured intracranial aneurysm. A preliminary clinical study.

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.

[Arachidonic acid metabolism following aneurysm rupture]. / Arachidonsäure-Metabolismus nach Aneurysmaruptur.

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.

Alteration of thromboxane and prostacyclin levels in experimental spinal cord injury.

We measured levels of thromboxane B2 and 6-keto-PGF1 alpha in rabbit spinal cord and cat CSF after impact injury to spinal cord. Rabbit tissue thromboxane B2 levels increased more than 6-keto-PGF1 alpha. In cat, CSF thromboxane B2 was higher the first hour postinjury; CSF 6-keto-PGF1 alpha also increased, but less so. These results imply activation of arachidonic acid metabolism. The relatively greater increase of thromboxane B2 suggests that thromboxane-prostacyclin imbalance may contribute to post-traumatic ischemia.