Effects of the 3-hydroxyanthranilic acid analogue NCR-631 on anoxia-, IL-1?- and LPS-induced hippocampal pyramidal cell lossin vitro

Luthman, Johan; Radesäter, Ann-Cathrin; Öberg, Caroline

doi:10.1007/bf01345273

Cited by 21 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, inasmuch as intraperitoneal injection of LPS at a dosage of 4 mg/kg kills newborn guinea pigs within 6 h, such mechanisms seem to be of minor importance in the present study. Nevertheless, delayed cell injury may explain some 534 discrepancies between our results and studies in adult animals and completely differentiated cell cultures in which LPSinduced injury was observed (25)(26)(27)(28)(29)(30). In addition, if LPS is exclusively toxic to a certain cell type, e.g.…”

Section: Lipopolysaccharides and Fetal Brain Damagecontrasting

confidence: 58%

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

et al. 2000

View full text Add to dashboard Cite

The aim of the present study was to clarify whether endotoxins [lipopolysaccharides (LPS)] have a toxic effect on fetal brain tissue after cerebral ischemia, while excluding their effect on the cardiovascular system. Experiments were therefore performed on hippocampal slices prepared from mature fetal guinea pigs. In particular, we studied the influence of LPS on nitric oxide production, energy metabolism, and protein synthesis after oxygen-glucose deprivation (OGD). Incubating hippocampal slices in LPS (4 mg/L) for as long as 12 h did not alter cGMP tissue concentrations significantly. However, 10 min after OGD of 40-min duration, cGMP tissue concentrations were substantially increased in relation to controls, and this increase was almost completely blocked by the application of 100 M N -nitro-Larginine, indicating that nitric oxide synthase was activated after OGD in fetal brain tissue. Again, LPS did not have any effect on cGMP tissue concentrations after OGD. Furthermore, addition of LPS altered neither protein synthesis nor energy metabolism measured 12 h after OGD. We therefore conclude that, apart from their well-known influence on the cardiovascular system, LPS do not alter metabolic disturbances in hippocampal slices of fetal guinea pigs 12 h after OGD. A direct toxic effect of LPS on immature brain tissue within this interval does not therefore seem to be very likely. However, delayed activation of LPS-sensitive pathways that may be involved in cell death, or damage limited to a small subgroup of cells such as oligodendrocyte progenitors, cannot be fully excluded. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity, including long-term neurologic sequelae in term and preterm fetuses. On the other hand, there is increasing evidence that perinatal brain damage is caused not only by hypoxic-ischemic insults, but also by ascending intrauterine infection before or during birth (1). Infants whose amnion is acutely inflamed are at a much greater risk of developing brain injury than control subjects (2, 3). However, it remains unclear whether fetal brain damage is the result of cerebral hypoperfusion caused by circulatory decentralization owing to severe endotoxemia or is caused by a direct effect of endotoxins on cerebral tissue (4). The present study was therefore set up to clarify whether endotoxins (LPS) have a direct toxic effect on fetal brain tissue after cerebral ischemia, while excluding their effects on the cardiovascular system. For this purpose we used the in-vitro system of OGD in hippocampal slices prepared from mature guinea pig fetuses (5, 6). In particular, we studied the influence of LPS on NO production, energy metabolism, and protein synthesis after OGD. Prolonged inhibition of protein synthesis after OGD seems to be an especially sensitive early marker of ischemic cell injury (7). METHODSThe present study was performed on guinea pigs, a precocious species, at 0.9 gestation (term, 68 d). The dams were anesthetized with halothane and decapitated,...

show abstract

Section: Lipopolysaccharides and Fetal Brain Damagecontrasting

confidence: 58%

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Anti-GSK3␤ was from Transduction Laboratories. The peptide ␤-amyloid 25-35 was from Bachem and was prepared as described previously (48,49). The biotinylated eukaryotic initiation factor 2B (eIF2B) peptide, biotin-AAEELDSRAGS(PO 3 H 2 )PQL, was synthesized at AstraZeneca R&D Lund (Lund, Sweden).…”

Section: Methodsmentioning

confidence: 99%

“…Organotypic cultures were prepared essentially according to Studer et al (48), with modifications described by Luthman et al (49). Threeday postnatal Sprague-Dawley rat pups were sacrificed by decapitation and their brains removed under sterile conditions.…”

Section: Neurodegeneration Mediated By ␤-Amyloid Peptide: Organotypicmentioning

confidence: 99%

Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418

Bhat

Xue

Berg

et al. 2003

Journal of Biological Chemistry

482

376

View full text Add to dashboard Cite

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC 50 ‫؍‬ 104 ؎ 27 nM), in an ATP-competitive manner (K i ‫؍‬ 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC 50 > 100 M) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3␤ protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by ␤-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.

show abstract

“…The differences found in hippocampal sensitivity to LPS may be due to a number of factors, including the properties of the test system used, regional variations in microglia density, or differences in sensitivity of various nerve cells to pro-inflammatory factors. We have previously been able to demonstrate that roller-drum slice cultures of hippocampus are sensitive to exposure to LPS derived from Salmonella abortus equi bacteria, causing a loss of pyramidal nerve cells (Luthman et al, 1998). This finding, as well as some of the studies referred to above, suggests that hippocampal neurons are indeed sensitive to exposure to LPS, leading to neurodegeneration.…”

Section: Introductionmentioning

confidence: 85%

Salmonella lipopolysaccharide (LPS) mediated neurodegeneration in hippocampal slice cultures

Johansson

Bohman²,

Radesäter

et al. 2005

neurotox res

View full text Add to dashboard Cite

Neuroinflammation has been suggested to play an integral role in the pathophysiology of various neurodegenerative diseases. Bacterial lipopolysaccharide (LPS) endotoxins are general activators of immune-cells, including microglial cells, which induce expression of pro-inflammatory factors. The aim of this study was to characterize neurodegenerative effects of exposure to LPS, derived from Salmonella abortus equi bacteria, in an in vitro brain slice culture system. Quasi-monolayer cultures were obtained using roller-drum incubations of hippocampal slices from neonatal Sprague Dawley rats for three weeks. Microglia/macrophages were identified in the monolayer cultures by CD11b immunostaining, while neuronal populations identified included N-methyl-D-aspartate (NMDA-R1) receptor immunoreactive pyramidal neurons and smaller GABA-immunoreactive cells. Following exposure to LPS (100 ng/ml) an increased density of CD11b positive cells was found in the cultures. In addition, the LPS exposure produced a concentration-dependent loss of the NMDA-R1 immunoreactive neurons in the cultures which was substantial at 100 ng/ml LPS. The loss of NMDA-R1 cells was apparent already after 24 h exposure to LPS and seemed to be primarily due to necrotic-like cell death. However, a continued loss of cells was found when cultures were analyzed at 72 h, concomitant with an increase in the expression of p53 in the NMDA-R1 cells and TUNEL labeling of a few cells. Also the number of GABA-immunoreactive cells decreased rapidly and to a substantial extent after 24 h exposure to LPS, with a continued decrease up to 72 h. The findings show that Salmonella LPS increases the density of CD11b positive cells and acts as a potent neurotoxin in hippocampal roller-drum slice cultures. The LPS-induced neurodegeneration has both necrotic- and apoptotic-like properties and appears to be non-selective, affecting both pyramidal and GABA neurons. LPS-induced neurotoxicity in slice cultures may be a useful system to study processes involved in inflammatory-mediated neurodegeneration.

show abstract

Effects of the 3-hydroxyanthranilic acid analogue NCR-631 on anoxia-, IL-1?- and LPS-induced hippocampal pyramidal cell lossin vitro

Cited by 21 publications

References 20 publications

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418

Salmonella lipopolysaccharide (LPS) mediated neurodegeneration in hippocampal slice cultures

Contact Info

Product

Resources

About