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E Westerberg

Publications and source records attributed to E Westerberg.

At least 19 recordsLinked to original sources
PubMed1997

alpha-Trinositol prevents increased negativity of interstitial fluid pressure in rat skin and trachea induced by dextran anaphylaxis.

The new anti-inflammatory agent alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate), is suggested to act on the cellular adhesion receptor towards extracellular matrix components, the beta1-integrins, and may therefore represent a novel principle for therapy of the phenomena associated with acute inflammation. Increased negativity of interstitial fluid pressure (p(if)) is a major driving force for the rapid edema formation in trachea and skin associated with dextran anaphylaxis in the rat. We therefore used this experimental model to study the effect of alpha-trinositol in skin and trachea of pentobarbital anesthetized rats. p(if) was measured with sharpened glass capillaries (3-7 microm) connected to a servocontrolled counterpressure system. alpha-Trinositol (10 mg) was given before or after dextran. Circulatory arrest was induced 2 min after i.v. dextran to limit the increased capillary fluid filtration associated with the anaphylactic reaction. This increased filtration will otherwise raise interstitial volume and thereby p(if) and cause an underestimation of a potential increased negativity of p(if). In the trachea, p(if) was 0.0 +/- 1.0 mmHg (S.D.) and -1.4 +/- 0.5 mmHg in controls given saline vehicle and alpha-trinositol (P > 0.05), respectively, and fell to -8.5 +/- 2.7 mmHg after dextran (P < 0.01). alpha-Trinositol given 2 min prior to or after dextran resulted in p(if) of -1.7 +/- 1.2 mmHg (P > 0.05 versus control, P < 0.01 versus dextran) and -4.7 +/- 3.0 mmHg (P < 0.01 versus control and dextran), respectively. In skin, i.v. dextran caused p(if) to fall from -0.6 +/- 0.5 to -4.6 +/- 1.9 mmHg (P < 0.001). When alpha-trinositol was given prior to dextran the corresponding figures were -0.4 +/- 0.8 and -0.9 +/- 1.1 mmHg, respectively (P > 0.05). Subdermal administration of alpha-trinositol after i.v. dextran and circulatory arrest normalized p(if) in concentration of 100, 10 and partly at 1 mg/ml. Thus, alpha-trinositol prevented the increased negativity of p(if) induced by dextran anaphylaxis when administered prior to as well as after dextran showing that the alpha-trinositol also could influence an already started inflammatory reaction.

Anaphylaxis↗
PubMed1996

Binding sites for alpha-trinositol (inositol 1,2,6-trisphosphate) in porcine tissues; comparison with Ins(1,4,5)P3 and Ins(1,3,4,5)P4-binding sites.

1. The molecular mechanism of action of the inositol trisphosphate isomer, alpha-trinositol (Ins(1,2,6)P3) which has potential therapeutic use in treatment of inflammation and burn oedema, is still unclear. Therefore we have studied binding sites for alpha-trinositol in different tissues. 2. In membranes from pig cerebellum, liver, kidney, heart, and spleen, the density of specific [3]-alpha-trinositol binding sites was maximal at pH 5.0. Cerebellum and spleen showed only one binding site (cerebellum KD = 9.1 microM, spleen KD = 7.3 microM). In the other tissues, there were a high-affinity site (heart KD = 70 nM, liver KD = 790 nM and kidney KD = 1800 nM), besides a low-affinity site with a KD ranging between 32 and 120 microM. In cerebellar membranes, the affinity and density (107 pmol mg-1 protein) of alpha-trinositol binding sites were not affected by phosphate (0 to 25 mM). 3. Binding of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 to membranes from different porcine tissues was also determined. Ins(1,3,4,5)P4, the isomer stereochemically related to alpha-trinositol, binds with an affinity of 1.2 nM in cerebellum, but in the other tissues the binding site density was too low to determine the affinity. With cerebellar membranes heterologous displacement of [3H]-Ins(1,3,4,5)P4 by alpha-trinositol yielded a K1 of 11 microM. The Ins(1,4,5)P3 receptor displayed an affinity of 15 nM in cerebellum and of 5 to 7 nM in the other tissues investigated. 4. The solubilized Ins(1,3,4,5)P4 receptor preparation from cerebellum did not show Ins(1,2,6)P3 binding. Ins(1,2,6)P3 binding was found in the pellet obtained after solubilization of the membranes with the detergent Brij 58. 5. Thus, in different tissues alpha-trinositol binds to proteins with different affinity. They are obviously not related to binding sites for Ins (1,4,5)P3 or for Ins(1,3,4,5)P4. Future experiments have to unravel the identity of the binding protein(s) for alpha-trinositol.

Animals↗
PubMed1996

Lowering of interstitial fluid pressure will enhance edema in trachea of albumin-sensitized rats.

Interstitial fluid pressure (Pif) has recently been found to play an important role in edema formation in acute airway inflammation. Because airway inflammation is important in the pathogenesis of asthma, Pif was measured in rat trachea after albumin challenge to rats previously sensitized to chicken egg albumin. In pentobarbital anesthesia (50 mg/kg intraperitoneally) sensitized rats received an intravenous infusion of either saline or albumin, which circulated for 4 min. Circulatory arrest was then induced with saturated KCl intravenously to prevent further edema formation, which will increase Pif and thereby possibly cause an underestimation of an increased negativity of Pif. Pif was measured with sharpened glass capillaries (diameter 3-6 micrometer) connected to a servo-controlled counter pressure system. Pif was -1.3 +/- 0.4 mm Hg in controls and -5.8 +/- 0.5 mm Hg in sensitized rats (p < 0.01) after allergen challenge. Airway resistance was measured to verify the occurrence of airway narrowing and increased significantly in sensitized rats after allergen challenge but did not change in controls. The experimental anti-inflammatory drug, alpha-trinositol (D-myo-inositol-1,2,6-trisphosphate, 10 mg), given before or after allergen challenge abolished the increased negativity of Pif (p < 0.05), while hydrocortisone (6.25 mg) had no effect. Thus, allergen challenge is associated with a lowering of Pif, which was abolished by alpha-trinositol.

Airway Resistance↗
PubMed1990

Protection against ischemia-induced neuronal damage by the alpha 2-adrenoceptor antagonist idazoxan: influence of time of administration and possible mechanisms of action.

The protective effect of the alpha 2-receptor antagonist idazoxan against neuronal damage in the neocortex and in the hippocampal CA1 region was studied in rats exposed to 10 min of incomplete forebrain ischemia. When administered i.v. immediately after ischemia (0.1 mg/kg) and subsequently for 6 h (10 micrograms/kg/min), idazoxan significantly reduced neuronal damage in the hippocampus (from 84 to 26%) and in the vulnerable parts of the neocortex (from 15 to 1%). The bolus dose alone provided no significant protection. When idazoxan administration was delayed for 30 min, no significant protection was noticed in the neocortex, and the effect in the hippocampus was ambiguous. A transient elevation of plasma corticosterone levels was induced during ischemia. Idazoxan administration for 2 h did not affect postischemic changes in corticosterone levels compared with saline infusion. Idazoxan (10(-7)-10(-4) M) did not influence the in vitro binding to glutamate receptors in brain slices. Thus, the protective effect of idazoxan cannot be explained by suppression of the plasma corticosteroid levels or via an antagonistic effect on glutamate receptors. Idazoxan apparently protects neurons when given during the first hours of postischemic reperfusion, while histopathological necrosis of neurons becomes visible 48-72 h after ischemia. Detrimental processes causing delayed neuronal death occur in the early postischemic phase and can be influenced by adrenoceptor ligands. Idazoxan may protect by several mechanisms but probably exerts its protective postischemic effect mainly through an increased noradrenergic neuronal activity and an elevation of extracellular noradrenaline (NA) levels in the brain. The favorable effects of NA may either be due to inhibition of excitotoxic neurotransmission or activation of survival-promoting and trophic processes.

Adrenergic alpha-Antagonists↗
PubMed1990

Extracellular levels of quinolinic acid are moderately increased in rat neostriatum following severe insulin-induced hypoglycaemia.

Extracellular concentrations of the brain metabolite quinolinic acid, an endogenous excitotoxin, were monitored by microdialysis in rat neostriatum and hippocampus/cortex during and following a 30-min period of insulin-induced hypoglycaemia. During hypoglycaemia-induced isoelectricity, extracellular levels of quinolinic acid in the striatum (basal value, 1.1 +/- 0.3 pmol per 30-microliters fraction) were elevated 1.7 times as compared to the control period. Thirty to ninety minutes following hypoglycaemia a significant increase in extracellular quinolinic acid to 2.2 times basal level was noted. After 2 h recovery, the beginning of neuronal necrosis was observed in the dorsolateral striatum. Implantation of the dialysis probe did not influence the extent of neuronal damage. No changes in extracellular quinolinic acid levels were observed in the hippocampus/cortex. The data indicate that following a severe hypoglycaemic insult vulnerable striatal cells are exposed to hyperphysiological extracellular quinolinic acid concentrations over an extended period of time. Considering the pronounced susceptibility of rat striatal neurons to the toxin, the small but prolonged elevation in the extracellular levels of quinolinic acid could be of significance for the development of delayed neuronal death in hypoglycaemia.

Animals↗
PubMed1989

Changes in excitatory amino acid receptor binding in the intact and decorticated rat neostriatum following insulin-induced hypoglycemia.

An involvement of excitatory amino acid (EAA) transmitter-receptor interactions in the development of hypoglycemia-induced neuronal damage has been suggested. We report here on the binding to EAA receptors in the rat caudate nucleus and cerebral cortex, during and following severe insulin-induced hypoglycemia with an isoelectric EEG of 10 or 30 min duration. The binding of alpha-[3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [( 3H]AMPA) to quisqualate receptors, [3H]kainic acid (KA) to kainate receptors, and [3H]glutamate to N-methyl-D-aspartate (NMDA)-sensitive sites was determined by quantitative autoradiography. During EEG isoelectricity, AMPA binding was reduced by approximately 40%, which could represent quisqualate receptor desensitization. One hour following glucose-induced recovery, AMPA binding was no longer different from control level. As the recovery period was prolonged to 1 or 4 weeks, AMPA binding decreased. The decrease was more pronounced in the dorsolateral than in the ventromedial part of the striatum. This correlates with the distribution of neuronal damage, and probably reflects loss of receptor binding sites due to cell death. During the period of EEG silence there was a tendency toward an increase in NMDA displaceable glutamate binding. Following 4 weeks of recovery, binding to NMDA receptors was significantly decreased. Glutamate binding to NMDA-sensitive sites was remarkably resistant to neuronal necrosis and was not significantly different from control values in the dorsolateral caudate 1 week following the hypoglycemic coma. No changes in KA binding were found until 1 week posthypoglycemia, when a significant reduction in binding was noted in the lateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Dynamic changes of excitatory amino acid receptors in the rat hippocampus following transient cerebral ischemia.

The changes in excitatory amino acid receptor ligand binding induced by transient cerebral ischemia were studied in the rat hippocampal subfields. Ten minutes of ischemia was induced by common carotid artery occlusion combined with hypotension, and the animals were allowed variable periods of recovery ranging from 1 day to 4 weeks. The binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) to quisqualate receptors, 3H-kainic acid (KA) to kainate receptors, and 3H-glutamate to N-methyl-D-aspartate (NMDA) receptors as determined by quantitative autoradiography. One week following ischemia the CA1 region of the hippocampus displayed a severe (90%) dendrosomatic lesion with preservation of presynaptic terminals. This was associated with a 60% decrease in AMPA binding and a 25% decrease in glutamate binding to NMDA receptors. At 4 weeks postischemia, both AMPA and NMDA sites were greatly reduced. Although the dentate gyrus granule cells are resistant to an ischemic insult of this magnitude, this region showed marked changes in receptor binding. One week following ischemia, the AMPA and NMDA binding decreased by approximately 40 and 20%, respectively. Following 2 weeks of recovery, the NMDA binding was not significantly different from control level, while the AMPA binding remained depressed up to 4 weeks postischemia. The high density of KA binding sites in the inner molecular layer of the dentate gyrus was unaffected by the ischemic insult, despite an extensive degeneration of cells in the hilus of dentate gyrus which projects glutamatergic afferents to this area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Excitatory amino acid receptors and ischemic brain damage in the rat.

The excitatory amino acid glutamate has been suggested to be an important mediator of the selective CA1 hippocampal damage which follows transient cerebral ischemia. In order to evaluate the possible involvement of altered glutamate receptor regulation in the expression of the delayed neuronal necrosis following ischemia, we have determined the density of glutamate receptor subtypes in the rat hippocampus following transient ischemia. We report a transient reversible decrease in [3H]AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding sites (presumably representing quisqualate receptors) followed by a long term loss of binding at 2 days postischemia which precedes neuronal loss. In contrast, no change was noted in the N-methyl-D-aspartate or kainic acid binding sites over this time period.

Animals↗
PubMed1987

Regional differences in arachidonic acid release in rat hippocampal CA1 and CA3 regions during cerebral ischemia.

Changes in the levels of arachidonic acid during ischemia in selectively vulnerable areas of the hippocampus were studied in the rat brain. Since neurons in the CA1 region are more vulnerable to ischemia than neurons in the adjacent CA3 region, the release of arachidonic acid in these two regions was measured during decapitation ischemia of 4- to 12-min duration. The concentration of free arachidonic acid increased with the duration of ischemia in both regions. However, the level was significantly higher in CA1 than in CA3 after 8 and 12 min of ischemia. This difference in arachidonic acid accumulation may reflect differences between the regions in agonist-dependent phospholipid breakdown as well as calcium-dependent phospholipase activity. The importance for the development of neuronal necrosis is discussed.

Animals↗
PubMed1986

Lesions to the corticostriatal pathways ameliorate hypoglycemia-induced arachidonic acid release.

The concentrations of free fatty acids (FFAs) in the neostriatum of control rats and rats subjected to unilateral cortical ablation were measured during and following severe insulin-induced hypoglycemia. The total FFA concentration in the caudate nucleus contralateral to the lesion increased to approximately 1.5 and 3 times the control level after 5 and 30 min of isoelectricity, respectively, and was similar to the control value following 1 h of recovery. After 5 min of isoelectricity, the total FFA pool was significantly smaller in the decorticated striatum. No difference between hemispheres was noted after 30 min of isoelectricity. After 5 min of isoelectricity the levels of stearic and arachidonic acid were selectively increased whereas palmitic acid and oleic acid remained at control levels. In the decorticated striatum of lesioned animals the arachidonic acid concentration was significantly lower, whereas the level of stearic acid was not significantly different from the control value. After 30 min of isoelectricity the levels of all four FFA species were increased. Apart from a significantly lower level of oleic acid on the decorticated side, there were no interhemispheric differences in the FFA levels. Since the early interhemispheric differences in the FFA levels. Since the early interhemispheric hemispheric differences in the levels of arachidonic and stearic acids coincide with a selective decrease in the levels of glutamate and a decreased energy utilization on the decorticated side, the results suggest that glutamate release during hypoglycemia induces an early receptor-mediated degradation of phospholipids, presumably via the phosphatidylinositol cycle.

Animals↗
PubMed1986

Effect of insulin-induced hypoglycemia on the concentrations of glutamate and related amino acids and energy metabolites in the intact and decorticated rat neostriatum.

The glutamate (Glu) terminals in rat neostriatum were removed by a unilateral frontal decortication. One to two weeks later the effects of insulin-induced hypoglycemia on the steady-state levels of amino acids [Glu, glutamine (Gln), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine] and energy metabolites (glucose, glycogen, alpha-ketoglutarate, pyruvate, lactate, ATP, ADP, AMP, phosphocreatine) were examined in the intact and decorticated neostriatum from brains frozen in situ. The changes in the metabolite levels were examined during normoglycemia, hypoglycemia with burst-suppression (BS) EEG, after 5 and 30 min of hypoglycemic coma with isoelectric EEG, and 1 h of recovery following 30 min of isoelectric EEG. In normoglycemia Glu decreased and Gln and glycogen increased significantly on the decorticated side. During the BS period no significant differences in the measured compounds were noted between the two sides. After 5 min of isoelectric EEG Glu, Gln, GABA, and ATP levels were significantly lower and Asp higher on the intact than on the decorticated side. No differences between the two sides were found after 30 min of isoelectric EEG. After 1 h of recovery from 30 min of isoelectric EEG Glu, Gln, and glycogen had not reached their control levels. Glu was significantly lower, and Gln and glycogen higher on the decorticated side. The Asp and GABA levels were not significantly different from control levels. The results indicate that the turnover of Glu is higher in the intact than in decorticated neostriatum during profound hypoglycemia.

Amino Acids↗
PubMed1985

Lesions of the glutamatergic cortico-striatal projections in the rat ameliorate hypoglycemic brain damage in the striatum.

Unilateral ablations of the motor cortex were performed on rats. One to two weeks following the ablation they were subjected to 30 min of reversible insulin-induced hypoglycemic coma. The levels of glutamate, aspartate, gamma-aminobutyric acid (GABA), taurine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and phosphocreatine (PCr) were determined in frozen tissue sections from the superior half of the caudate nucleus. The lesions induced a specific reduction in the levels of glutamate by approx. 10% in the dorsal caudate nucleus ipsilateral to the lesion, while no significant differences in the levels of aspartate, GABA, taurine, ATP, ADP, AMP or PCr were noted. Neuronal necrosis in the caudate nucleus in animals subjected to 30 min of insulin-induced hypoglycemic coma and one week recovery was assessed by light microscopy. Contralateral to the lesion, extensive neuronal necrosis, mainly affecting small and medium-sized neurons, was observed in the dorsal and lateral caudate nucleus. In the caudate ipsilateral to the lesion a complete amelioration of necrosis was noted in areas subjacent to the lesion. The data suggest that hypoglycemic brain damage is induced by excitotoxins such as glutamate or related compounds.

Animals↗
PubMed1985

Influence of acidosis on lipid peroxidation in brain tissues in vitro.

To study the influence of acidosis on free radical formation and lipid peroxidation in brain tissues, homogenates fortified with ferrous ions and, in some experiments, with ascorbic acid were equilibrated with 5-15% O2 at pH values of 7.0, 6.5, 6.0, and 5.0, with subsequent measurements of thiobarbituric acid-reactive (TBAR) material, as well as of water- and lipid-soluble antioxidants (glutathione, ascorbate, and alpha-tocopherol) and phospholipid-bound fatty acids (FAs). Moderate to marked acidosis (pH 6.5-6.0) was found to grossly exaggerate the formation of TBAR material and the decrease in alpha-tocopherol content and to enhance degradation of phospholipid-bound, polyenoic FAs. These effects were reversed at pH 5.0, suggesting a pH optimum at pH 6.0-6.5. It is concluded that acidosis of a degree encountered in ischemic brain tissues has the potential of triggering increased free radical formation. This effect may involve increased formation of the protonated form of superoxide radicals, which is strongly prooxidant and lipid soluble, and/or the decompartmentalization of iron bound to cellular macromolecules like ferritin.

Acidosis↗
PubMed1985

Effects of two convulsant beta-carboline derivatives, DMCM and beta-CCM, on regional neurotransmitter amino acid levels and on in vitro D-[3H]aspartate release in rodents.

Clonic seizures were induced in Swiss or DBA/2 mice by methyl-6-7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), 0.048 mmol/kg i.p., or by methyl-beta-carboline-3-carboxylate (beta-CCM), 0.044 mmol/kg i.p. Measurement of regional brain (cortex, hippocampus, striatum, and cerebellum) amino acid levels after 15 min of seizure activity showed increases in gamma-aminobutyric acid (GABA) (in all regions after beta-CCM, and in cortex and hippocampus after DMCM), and an increase in glycine in the striatum after beta-CCM. Aspartate levels fell (in cortex and hippocampus) after DMCM, but were unchanged in all regions after beta-CCM. Glutamate levels fell in cortex after beta-CCM and in striatum after DMCM. Pretreatment with the excitatory amino acid receptor antagonist, 2-amino-7-phosphonoheptanoic acid, 0.5 mmol/kg i.p., 45 min prior to the beta-carboline, significantly increased the ED50 for DMCM-induced clonic seizures (4.68 mumol/kg vs. 9.39 mumol/kg). Similar pretreatment did not significantly alter the ED50 for beta-CCM (4.22 mumol/kg vs. 6.6 mumol/kg). Pretreatment with 2-amino-7-phosphonoheptanoic acid, 1.0 mmol/kg, blocked the increase in GABA content produced by DMCM but not the fall in cortical aspartate content. Potassium-induced release of preloaded D-[3H]aspartate from rat cortical or hippocampal minislices was enhanced in the presence of DMCM (100 microM). In contrast, stimulated release of D-[3H]aspartate (from cortex or hippocampus) was not altered in the presence of beta-CCM (100 microM). Although DMCM and beta-CCM are both considered to induce convulsion by acting at the GABA--benzodiazepine receptor complex, the convulsions differ in several pharmacological and biochemical respects. It is suggested that enhanced release of excitatory amino acid neurotransmitters plays a more important role in seizures induced by DMCM.

2-Amino-5-phosphonovalerate↗