CNS stimulation and PGE2 release. III. Pentamethylenetetrazole-induced seizures.

Measurement of prostaglandin E2 (PGE2) in the ventriculocisternal perfusate of the halothane anesthetized, artificially ventilated cat has revealed low but measurable levels of the prostanoid (64 +/- 5 pg/min). Administration of pentamethylenetetrazole (PTZ) resulted in a rapid appearance of paroxysmal bursting, the magnitude and duration of which was dose dependent. During the 30-min interval after seizure initiation, PGE2 secretion rates into the ventriculocisternal perfusate rose by five- to sevenfold. Though the initial rate of PGE2 secretion correlated closely with the initial magnitude of bursting, there were significant differences, viz. the time courses. Thus, after a low dose of PTZ (200 mg/kg) the increase and return to normal of PGE2 secretion was time locked with the onset and offset of seizures. In contrast, after high doses of PTZ (250 mg/kg i.v.), seizure activity returned to near baseline by 90 min, while the levels of PGE2 secretion remained elevated for periods in excess of 150 min. Pretreatment with clonazepam (CLP: 3 mg/kg i.v. infusion) blocked seizures otherwise induced by PTZ (250 mg/kg) and the increase in PGE2 secretion. CLP administration 60 min after the initiation of seizures, blocked further seizure activity but did not alter the elevated secretion of PGE2. We thus believe these data jointly support the hypothesis that under intense paroxysmal bursting there is a change in neuronal state such that large stores of free fatty acids are available either because they have accumulated during the seizure because of a continued Ca2+ influx or the presence of large and continuing concentrations of Ca2+ accumulating in the cytosol secondary to energy failure.

Release of prostaglandin E2 from brain of cat: II. In vivo studies on the effects of adrenergic, cholinergic and dopaminergic agonists and antagonists.

This study examined the effect of several neurotransmitters, receptor agonists and antagonists on the release of prostaglandin E2 (PGE2) from brain. Levels of PGE2 were measured in consecutive 30-min samples, collected from ventriculocisternal perfusions (100 microliters/min) in chloralose-urethanized cats, before, during and after the addition of carbachol, norepinephrine (NE) and dopamine (DA). Samples were submitted to acid organic extraction and radioimmunoassay (RIA) with a specific antibody. Displacement curves of ligand binding with control and stimulated samples were parallel to those observed with PGE2. The addition of carbachol (10(-4) M) to the perfusate resulted in a significant increase in the levels of PGE2 from 600 +/- 259 pg PGE2/min during the control period up to 1306 +/- 429 pg PGE2/min during the perfusion (P less than 0.02). Though NE (10(-3) M) and isoproterenol (10(-3) M, beta) were without effect, methoxamine (10(-3) M, alpha 1), but not ST-91 (an alpha 2-agonist), produced an increase in secretion of PGE2. This increase was blocked by phentolamine (10(-3) M). The addition of DA (10(-4) M) produced a fall from control levels of 642 +/- 185 pg PGE2/min to 290 +/- 101 pg PGE2/min (P less than 0.02). These results suggest that the central activation of selected populations of receptors will alter basal levels of PGE2 in the extracellular space.

Production of uric acid in cerebrospinal fluid after subarachnoid hemorrhage in dogs: investigation of the possible role of xanthine oxidase in chronic vasospasm.

Based on accumulating evidence of the role of xanthine oxidase (XO) in generating oxygen free radicals and causing tissue damage during ischemia, we examined the possible role of XO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). After inducing SAH in dogs by two autologous blood injections 2 days apart, chronic vasospasm of the basilar artery was reliably produced. There was a 3.5-fold elevation in uric acid (UA), the product of XO, in the cerebrospinal fluid (CSF) of these animals. Parenteral administration of allopurinol (i.v., 25 mg/kg, every 6 hours), a specific blocker of XO, successfully abolished the elevation in CSF uric acid levels due to SAH. However, angiographic vasospasm measured on Day 7, morphological changes observed by electron microscope, and elevated CSF prostaglandin levels were not altered by the treatment. It can be concluded that the observed activation of the enzyme XO, which is a well-known source of oxygen free radicals in ischemia in various organs, is not playing a major role in the pathogenesis of chronic cerebral vasospasm in this animal.

Measurement of prostaglandins in the cerebrospinal fluid in cat, dog, and man.

Prostaglandins are involved in the modulation of various central functions (neurotransmitters and hypothalamic hormone release, thermoregulation, cerebrovascular tone) and their levels increase in pathological situations [subarachnoid hemorrhage (SAH), stroke, convulsive disorders, etc.]. This study, using sensitive and specific antibodies, examined levels of four eicosanoids, prostaglandins E2 and F2 alpha (PGE2, PGF2 alpha); and the metabolites of PGI2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and of thromboxane A2, thromboxane B2 (TxB2), in the cerebrospinal fluid (CSF) obtained atraumatically from three species (human, canine, and feline). An assessment of the methodologic procedures (extraction and radioimmunoassay) was carried out. Human lumbar cerebrospinal fluid was shown to contain PGF2 alpha (15-44 pg/ml), 6-keto-PGF1 alpha (undetectable to 39 pg/ml), and TxB2 (undetectable to 28 pg/ml), whereas PGE2 was undetectable (less than 18 pg) in all cases. In both animals species the eicosanoid concentrations were 3- to 30-fold higher than humans for every prostaglandin examined. Although the prostaglandin profile for a given species remained constant (cat, PGE2:6-keto-PGF1 alpha:TxB2:PGF2 alpha; dog, TxB2:PGE2:6-keto-PGF1 alpha:PGF2 alpha), the absolute levels were found to be lower in the pentobarbital-anesthetized animals than in conscious cats. The correspondence of the prostaglandin profiles found in cerebrospinal fluid with the profiles reported in the literature in brain homogenates for the same species supports the hypothesis that cerebrospinal fluid levels of prostaglandins reflect the relative rates of synthesis in neural tissue.