Gliotoxic action of glutamate on cultured astrocytes.

Because of the well-documented importance of glutamate clearance by astrocytes in protecting neurons against excitotoxicity, it was interesting to examine whether L-glutamate exerts a toxic action on cultured astrocytes. Cell damage was evaluated by measuring activity of lactate dehydrogenase (LDH) released into the culture medium. Exposure of astrocyte cultures of the neonatal rat cerebral cortex to L-glutamate resulted in a concentration- and time-dependent increase in the release of LDH. L-Glutamate-induced gliotoxicity appeared to be mediated predominantly by the increase of oxidative stress because the reduced glutathione content and its effects were almost completely blocked by vitamin E and pyrrolidinedithiocarbamate. To support this notion further, the supplementation or depletion of intracellular reduced glutathione content attenuated or worsened L-glutamate toxicity, respectively. Activation of the glutamate transporter mimicked the action of L-glutamate on astrocytes. In addition, degrees of cell damage were not directly correlated to the levels of glutamate uptake. Moreover, the mechanism of this toxicity required energy and macromolecular synthesis. Taken together, brief exposure to L-glutamate resulted in glutamate uptake and cell swelling, whereas sustained exposure injured astrocytes via oxidative stress instead of the excitatory mechanism.

Pallister-Hall syndrome: clinical and MR features.

A 4-month-old boy with polydactyly and bifid epiglottis was found to have a large sellar and suprasellar mass. When the diagnosis of Pallister-Hall syndrome was made, conservative management was elected. When the patient was 2 years old, the tumor had grown proportionally with the patient, and he was developing appropriately. Although rare, this entity is important to recognize not only for clinical diagnosis but also for appropriate management and genetic counseling.

Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults.

The effect of supplementation with vitamins C and E on cytokine production of healthy adult volunteers was studied in a single-blind trial. Ten subjects in each group received daily vitamin C (1 g ascorbic acid), vitamin E (400 mg dl-alpha-tocopheryl acetate), or vitamins C and E for 28 d. Plasma concentrations of alpha-tocopherol, ascorbate, and lipid peroxides as well as the production of cytokines by peripheral blood mononuclear cells (PBMCs) were measured before, during, and at the end of the supplementation and 1 wk later. PBMCs were cultured in the presence of absence of lipopolysaccharide for 24 h. The interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) in the culture supernates were assayed by enzyme-linked immunosorbent assay methods. Production of IL-1 beta and TNF-alpha in the group supplemented with vitamins C and E was significantly higher (P < 0.05) than that of the groups given vitamin E or vitamin C alone. The enhancing effect of supplementation with a combination of vitamins E and C coincided with peak plasma alpha-tocopherol and ascorbate concentrations and the lowest plasma lipid peroxide concentrations (P < 0.05) on day 14. In addition, an in vitro experiment with PBMCs showed that vitamins E and C reduced lipopolysaccharide-induced prostaglandin E2 production and enhanced TNF-alpha production. These results indicate that combined supplementation with vitamins C and E is more immunopotentiating than supplementation with either vitamin alone in healthy adults.

Inhibition of plasma extravasation by abruquinone A, a natural isoflavanquinone isolated from Abrus precatorius.

Polymyxin B-induced hind-paw edema was suppressed by abruquinone A, an isoflavanquinone isolated from Abrus precatorius, in normal as well in adrenalectomized mice. Unlike dexamethasone, abruquinone A did not increase the liver glycogen content in fasting adrenalectomized mice. The volume of exuded plasma was significantly reduced by abruquinone A in neurogenic inflammation, passive cutaneous anaphylactic reaction and compound 48/80-induced ear edema. Histamine-, serotonin-, bradykinin- and substance P-induced plasma extravasation in ear edema was also suppressed by abruquinone A. Abruquinone A, like isoproterenol, significantly reduced the bradykinin- and substance P-induced plasma extravasation in normal as well as in compound 48/80-pretreated mice. In addition, abruquinone A suppressed the bradykinin- and substance P-induced ear edema to a significantly greater extent than diphenhydramine/methysergide did. In the in vitro experiments, abruquinone A suppressed the compound 48/80-induced histamine and beta-glucuronidase released from isolated rat peritoneal mast cell preparations. These results suggest that the anti-inflammatory effect of abruquinone A is mediated partly via the suppression of the release of chemical mediators from mast cells and partly via the prevention of vascular permeability changes caused by mediators. The glucocorticoid activity and the release of glucocorticoid hormones from the adrenal gland are probably not involved.

Antiarrhythmic action of naloxone. Suppression of picrotoxin-induced cardiac arrhythmias in the rat.

The antiarrhythmic properties of the opiate antagonist naloxone have been reported in a variety of models of arrhythmia. To determine the generality and the possible central involvement of its antiarrhythmic activity, the effects of naloxone were assessed against cardiac arrhythmias induced by intravenous bolus injections of picrotoxin. Naloxone at doses of 0.33 and 1 mg/kg significantly reduced the incidence and severity of picrotoxin-induced arrhythmias in a dose-related manner, without alteration of blood pressure and heart rate. The results demonstrate the antiarrhythmic efficacy of naloxone in an additional animal model. They further suggest that the antiarrhythmic actions of naloxone may be mediated by the central nervous system via both the autonomic and GABAergic pathways.

The hypotensive and negative chronotropic effects of dehydroevodiamine.

The cardiovascular effects of dehydroevodiamine, an alkaloid isolated from Evodia rutaecarpa Jussieu, were studied in both in vivo and in vitro experiments. The in vivo experiments revealed that i.v. administration of dehydroevodiamine elicited a slight but significant reduction in blood pressure and a marked decrease in heart rate which was confirmed by an increased cycle length of the electrocardiogram. However, a hemodynamic experiment with microspheres showed that the total peripheral resistance was not altered by dehydroevodiamine. The blood flows of various organs were not significantly changed except those of kidney and skin, in which blood flow was decreased. In vitro, the spontaneously beating atria were significantly suppressed by dehydroevodiamine in a dose-dependent manner. These findings suggested an important effect of dehydroevodiamine in suppressing the heart, which may largely contribute to the hypotensive effect of this alkaloid. However, its vasodilator effect on hindquarter muscles cannot be neglected.

Clonidine suppresses digitalis-induced ventricular tachycardia in cats.

Effects of intravenous (IV) and intravertebral arterial (IA) administrations of alpha-2 adrenoceptor agonist, clonidine (CLO) and its antagonist, yohimbine (YOH, 0.05 mg/kg, IA), on the ventricular tachycardia (VT) induced with IV acetyl strophanthidin (AS) were studied in cats anesthetized with intraperitoneal chloralose. IVAS does-dependently produced cardiac arrhythmias including complete atrioventricular conduction block (118 +/- 14 micrograms/kg), junctional tachycardia (128 +/- 20 micrograms/kg), multiform ventricular premature beats (157 +/- 21 micrograms/kg) and sustained VT (220 +/- 23 micrograms/kg). IACLO dose for terminating VT induced with IVAS was about one fifth of IVCLO dose. IACLO dose for terminating VT induced with IVAS + IVYOH was significantly higher than that in VT induced with IVAS (14.8 +/- 3.7 vs 5.8 +/- 1.0 micrograms/kg, p less than 0.005). These experiments clearly demonstrated that IAYOH specifically antagonized the antiarrhythmic effect of IA CLO on the AS-induced VT. Since small dose of IA administration of the drugs acts mainly on the central nervous system, we suggest that the antiarrhythmic effect of CLO on AS-induced VT is likely through the central alpha-2 adrenoceptor.

A modified formula of GIK (glucose-insulin-potassium) therapy for treatment of extensive burn injury in dogs.

The effectiveness of a modified glucose-insulin-potassium (GIK) formula, which was derived from the results of a previous study (the maximal glucose disposal rate of 400 mg/M2/min required an insulin infusion rate at 1,200 mU/M2/min and KCl supplement rate at 0.08 mEq/M2/min), was evaluated in the treatment of extensive acute burn injury (EABI) in dogs. Under anesthesia initially with intravenous sodium pentobarbital 35 mg/kg followed by a maintenance dose of 5 mg/kg/hr, a third-degree burn of about 50% of the total body surface was created by acetylene torch over the ventral wall of the chest and abdomen. Cardiovascular parameters including heart rate, mean arterial blood pressure, pulmonary wedge pressure, cardiac index, and cardiac contractility (dP/dt of left ventricular pressure), as well as blood chemical data of pH value and K+ concentration were monitored. The present GIK therapy in EABI dogs effectively prevented a decrease in cardiac function, markedly enhanced cardiac function, steadily prolonged cardiac enhancement, and safely avoided hypoglycemic attack.