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PubMed1994

Serum gangliosides in mice with metastatic and non-metastatic brain tumors.

The content of serum gangliosides was examined in VM and C57BL/6J (B6) mice that contained subcutaneous metastatic (VM) and non-metastatic (CT-2A) brain tumors, respectively. Gas-liquid chromatography (GLC) and high performance thin-layer chromatography (HPTLC) were used to analyze the serum gangliosides. N-glycolylneuraminic acid (NeuGc) accounted for greater than 90% of the total serum sialic acid content in each mouse strain (5.53 nmol and 2.05 nmol per ml serum, respectively). GM2-NeuGc was the major serum ganglioside detectable in both the normal and tumor-bearing mice of each strain. Shedding of tumor gangliosides into the serum occurs in various murine non-neural tumors and in human gliomas and neuroblastomas, but has not been previously studied in murine brain tumors. Our results show that serum ganglioside concentration was reduced in VM mice bearing the metastatic VM tumor, but was increased in B6 mice bearing the non-metastatic CT-2A tumor. These changes in concentration, however, were not associated with marked changes in serum ganglioside distribution. As serum gangliosides are synthesized in the liver, the differences in serum ganglioside concentration in the tumor-bearing mice may arise more from changes in liver function than from differences in tumor shedding.

Animals↗
PubMed1997

Ganglioside shedding and changes in ceramide biosynthesis in human ovarian tumors.

The contents and composition of ceramides and gangliosides were measured in human ovarian tumors (benign and malignant) and sera of tumor patients. In tumors (especially malignant) the content of ceramides is decreased compared to that in normal tissue, and the malignant tumor ceramides contain significant amounts of sphinganine which is absent in the ceramides of normal tissue, suggesting an alteration in ceramide biosynthesis. The content of gangliosides in tumors is also decreased. The major gangliosides of normal and tumor ovarian tissues are GM3 (sialocsyllactosyl ceramide) and GD3 (disialosyllactosyl ceramide). In tumors, the GD3 content is significantly decreased. The ceramide/ganglioside molar ratio in tumors is shifted toward gangliosides. In sera of tumor patients, ceramide content does not change, ganglioside content (especially that of GD3) increases compared to that in sera of healthy subjects due to ganglioside shedding from the surface of tumor cells, and the ceramide/ganglioside molar ratio decreases. These changes may stimulate tumor growth because of the opposite effects of ceramides and gangliosides: ceramides suppress tumor growth and gangliosides suppress antitumor activity.

Ceramides↗
PubMed1991

High-performance capillary electrophoresis of gangliosides.

Gangliosides are sialic acid-containing glycosphingolipids. In aqueous media, these glycolipids have been shown to exist as stable micelles. Ganglioside micelles could be analyzed by high-performance zonal capillary electrophoresis in uncoated fused-silica capillaries within 10 min. The mass sensitivity determined by monitoring the absorption of ultraviolet light at 195 nm was in the order of 10(-11) mol. Increasing the pH of the running buffer from 3.0 to 7.4 or the voltage from 10 to 30 kV increased the relative mobilities of gangliosides. By contrast, increasing the ionic strength of the buffer decreased the migration and broadened the elution peak widths of gangliosides. Ganglioside* micelles including GM1, GD1b, and GT1b were resolved into separate peaks by capillary electrophoresis at physiological pH shortly after mixing. Upon prolonged incubation, the ganglioside peaks merged to form a single species. The fusion process was temperature-dependent. At 50 degrees C, formation of mixed micelles between polysialogangliosides GD1b and GT1b was complete within 30 min. In contrast, no fusion of the ganglioside peaks was observed at 0 degrees C even after 75 h. Formation of mixed micelles between GD1b and other polysialogangliosides including GD1a, GT1b, and GQ1b at 37 degrees C required 1.5, 3.0, and 2.0 h, respectively. Formation of mixed micelles between monosialoganglioside GM1 and polysialogangliosides were 6- to 36-fold slower. No fusion was observed between monosialogangliosides GM1 and GM2 after 2 days of incubation. These findings indicate that polysialogangliosides may have higher propensities than monosialoganglioside to form mixed micelles.

Electrophoresis↗
PubMed1988

Serum antibodies to gangliosides in Guillain-Barré syndrome.

To determine whether antibodies to acidic glycolipids of nervous tissue are present in patients with Guillain-Barré syndrome (GBS), sera from patients with GBS and appropriate control subjects were tested by a thin-layer chromatogram overlay technique. Chromatograms on which the whole ganglioside fractions from peripheral nerve and brain had been separated were overlaid with appropriate dilutions of the patients' sera (1:100 or greater), and antibody binding was revealed with a radiolabeled or peroxidase-labeled second antibody. Antibodies to ganglioside antigens were detected in 5 of 26 patients with GBS. IgG antibodies in 1 patient reacted strongly with LM1 (sialosyl paragloboside), the major ganglioside of human peripheral nervous system myelin, and its hexaose analog (sialosyl lactosaminyl paragloboside), a minor ganglioside of human peripheral nervous system myelin. The antibody titer in this patient fell 8-fold over 6 weeks coincident with clinical improvement. IgG from 2 other patients with GBS reacted with GD1b ganglioside, and the antibody titers in these patients also decreased substantially with clinical improvement. IgM antibodies in the sera from 2 other patients reacted with GD1a and GT1b gangliosides, which have a shared terminal carbohydrate sequence. Antibodies to gangliosides were not detected in the sera from 19 patients with other neurological diseases or from 10 normal subjects, and the frequency with which antiganglioside antibodies occurred in the patients with GBS was significantly greater than that in the combined control subjects (p less than 0.01). The results demonstrate relatively high levels of antibodies to gangliosides in some GBS patients.

Adult↗
PubMed1984

Gangliosides stimulate protein synthesis, growth, and axon number of regenerating limb buds.

When a newt limb is amputated and begins to regrow, regenerating axons exert a neurotrophic influence on the limb regeneration process. Previous studies have shown that direct manipulation of limb nerves, by electrical stimulation or a conditioning lesion, elevates protein synthesis, increases neurotization and accelerates growth of the limb bud. Since exogenously supplied gangliosides accelerate axonal sprouting in regenerating nerves, we wanted to know whether gangliosides would similarly affect limb regeneration. To test this, regrowing limb buds were either infused with or immersed into gangliosides, or animals were injected intraperitoneally with gangliosides. Infused gangliosides elevated protein synthesis in limb buds 15% and increased the number of axons in limb buds 45% by 6 hours after infusion. Regenerating limb bud morphogenesis was initiated 3-4 days earlier in animals receiving i.p. injections of gangliosides every 12 hours. Similarly, limbs immersed daily in gangliosides began regrowth sooner than contralateral controls and this advantage was maintained throughout the period of observation. These findings indicate that treatment with gangliosides has a salutary effect on limb regeneration.

Animals↗
PubMed2004

Gangliosides activate microglia via protein kinase C and NADPH oxidase.

Microglia, the major immune effector cells in the central nervous system, are activated when the brain suffers injury. A number of studies indicate that gangliosides activate microglia. However, the signaling mechanisms involved in microglial activation are not yet to be elucidated. Our results show that gangliosides induce the expression of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in rat brain microglia and BV2 murine microglia via protein kinase C (PKC) and NADPH oxidase. Expression of IL-1beta, TNF-alpha, and iNOS in ganglioside-treated cells was significantly reduced in the presence of inhibitors of PKC (GF109203X, Go6976, Ro31-8220, and rottlerin) and NADPH oxidase (diphenyleneiodonium chloride [DPI]). In response to gangliosides, PKC-alpha, betaII, and delta and NADPH oxidase p67(phox) translocated from the cytosol to the membrane. ROS generation was also activated within 5 min of ganglioside treatment. Ganglioside-induced ROS generation was blocked by PKC inhibitors. Furthermore, ganglioside-induced activation of NF-kappaB, an essential transcription factor that mediates the expression of IL-1beta, TNF-alpha, and iNOS, was reduced in the presence of GF109203X and DPI. Our results collectively suggest that gangliosides activate microglia via PKC and NADPH oxidase, which regulate activation of NF-kappaB.

Animals↗
PubMed1996

A monoclonal antibody to human macrophage gangliosides inhibits macrophage migration.

Gangliosides have diverse immunoregulatory properties. The gangliosides endogenous to macrophages may have immunoregulatory properties that distinguish them from other gangliosides. Gangliosides have been indirectly implicated in macrophage migration as putative cell surface receptors for migration inhibitory factor (MIF). In this study, a monoclonal antibody to human macrophage gangliosides (antibody 25F4) was developed and characterized. This is the first report of the development of monoclonal antibodies to gangliosides of macrophages of any species. Thin-layer chromatographic immunostaining indicated that antibody 25F4 recognized major gangliosides of human macrophages but did not recognized those previously identified as containing fucose. Immunofluorescent surface labeling of viable human macrophages indicated that antibody 25F4 recognized a surface-accessible epitope, present on all cells, and that this was abolished with lipid depletion of macrophage membranes. This epitope was not present on several human nonmacrophage cells. Finally, human macrophages pretreated with antibody 25F4 demonstrated striking inhibition of migration of an agarose droplet assay, whereas an irrelevant monoclonal antibody or monoclonal antibodies to nonganglioside surface epitopes of human macrophages had no effect on migration. Migration inhibition occurred even though antibody 25F4 was removed from the extracellular milieu and was not due to formation of cellular aggregates. These studies support a role for human macrophage gangliosides in macrophage migration.

Antibodies, Monoclonal↗
PubMed1981

Synthesis of gangliosides by cultured oligodendrocytes.

Gangliosides are enriched in the nervous system compared to other tissues. The synthesis of gangliosides by monolayer cultures of isolated oligodendrocytes has not previously been investigated. Cells were labeled with [3H] galactose at preselected times and gangliosides isolated by phase partition, purified, and identified by chromatography. Cultured oligodendrocytes showed selectivity in their synthesis of gangliosides, which was expressed in the type of ganglioside synthesized as well as in the change of incorporation over time in culture. For the first ten days, there was very little incorporation of [3H] galactose in gangliosides, but this was followed by a stimulation of uptake for GM3, GM1/GD3, and GD1 gangliosides, reaching a maximum after approximately 25-30 days in vitro. There was little incorporation into GM2 or trisialogangliosides throughout the life of the cultures. Since oligodendrocytes synthesize extensive membranes during this period, one may speculate that the de novo-synthesized gangliosides are used for membranes.

Animals↗
PubMed1984

Analytical and preparative high-performance liquid chromatography of gangliosides.

Analytical and preparative procedures are described for high-performance liquid chromatography (HPLC) fractionation of gangliosides without previous derivatization. These procedures make use of a reversed-phase Lichrosorb RB-8 or mu Bondapak RP-18 column, and of a mixture of acetonitrile and 5 mM phosphate buffer, at fixed or varying volume ratios, as solvent system. Peak elution from the column is monitored by flow through reading of absorbance at 195 nm. Under all the described conditions HPLC is capable of resolving all common gangliosides and of separating each of them into four molecular species containing C18-sphingosine, C18-sphinganine, C20-sphingosine, or C20-sphinganine. The analytical method has been successfully applied to fractionation of ganglioside mixtures from calf brain and to verification of homogeneity of single-ganglioside preparations. It is suitable for quantitative purposes, with high sensitivity (detection limit, 0.1 nmole) and precision (SD less than 10% of mean values in the concentration range 0.1-50 nmoles). The semipreparative method, which provides successive cycles of analysis in a fully automated way, enables the preparation in 2-4 days of 100-mg amounts of each molecular species starting from single gangliosides, like GM1 and GD1a. The preparative method makes use of acetonitrile-phosphate buffer-tetrahydrofuran as eluting solvent, and requires the addition to the starting ganglioside of the corresponding radioactive compound as tracer. This procedure, applied to GM1 ganglioside, is devised for processing up to 50 mg of ganglioside per analysis.

Animals↗
PubMed1990

Effects of short- and long-term ganglioside treatment on the recovery of neurochemical markers in the ibotenic acid-lesioned rat striatum.

The striatum of adult rats was bilaterally lesioned with stereotaxic injections of ibotenic acid in a dose (16 nmoles) that resulted in subtotal lesions. Some rats received systemic ganglioside treatment starting the day before operation and lasting for 6 or 24 days after operation; they were compared with lesioned rat receiving systemic saline injections as well as with corresponding groups of sham-operated animals. Specific neurochemical markers for cholinergic neurons (choline acetyltransferase, ChAT), GABAergic neurons (glutamate decarboxylase; GAD), and astrocytes (glutamine synthetase; GS) were assayed to asses the neurochemical recovery promoted by ganglioside treatment. Twenty-four, but not six, days after operation a significant increase of ChAT and GAD was measured in the striatum of lesioned rats treated with gangliosides in comparison with the saline group. Furthermore, a significant increase of both enzymes occurred in the striatum of lesioned rats receiving ganglioside treatment for 24 days in comparison with rats receiving ganglioside treatment for 6 days only. A small but significant increase of ChAT was measured in the striatum of sham-operated rats after 24 days of ganglioside treatment in comparison with the corresponding saline group. Finally, the increase of GS caused by the glial reaction to the ibotenic acid lesion was not affected by ganglioside treatment. The results indicate that a relatively long-lasting ganglioside treatment stimulates the recovery of specific neuronal transmitter markers and that some effect is, in addition, exerted on unlesioned cholinergic striatal neurons.

Animals↗
PubMed1992

Protection of neuro-2a cells against calcium ionophore cytotoxicity by gangliosides.

Gangliosides are known to assert both neuritogenic and neuroprotective effects when applied to a variety of neuroblastoma and primary neuronal cultures. We have developed a model employing Neuro-2a neuroblastoma cells with Ca2+ ionophore A23187 as neurotoxic agent causing neurite retraction and eventual cell death. Gangliosides attenuated the toxicity of this substance, increasing both cell survival and neurite stability. In one series of experiments, cells were exposed to A23187 for 24 hr and then incubated in fresh medium (washout) for 18 hr; gangliosides were present at varying times. The paradigm in which cells were only preincubated (2 hr) with ganglioside provided no benefit, nor did incubation of the cells in both ionophore and ganglioside during the 24-hr exposure period. Significant protection was achieved by exposing the cells to ganglioside after washout of A23187, or continuously throughout the whole period. Bovine brain ganglioside mixture and the four major components (GM1, GD1a, GD1b, GT1b) applied individually were all effective. By contrast, GM3 and GM1-alcohol, a neutral derivative of GM1, provided little or no protection. Dichlorobenzamil, an inhibitor of the Na(+)-Ca2+ exchanger, tended to block the neurite stabilizing effect of gangliosides, suggesting that the mechanism might involve potentiation of this antiporter.

Animals↗
PubMed1995

Gangliosides have a bimodal effect on DNA synthesis in U-1242 MG human glioma cells.

GM1, GD1a, and GT1b inhibit both PDGF-stimulated and serum-stimulated DNA synthesis in Swiss 3T3 cells and the human glioma cell line U-1242 MG in a dose-dependent manner. The ganglioside inhibitory effect is counteracted in a dose-responsive fashion by serum such that ganglioside-induced inhibition is essentially abolished in 10% serum. Because of the potentially important role that gangliosides play in growth regulation of human gliomas, this phenomenon was studied in detail using U-1242 MG cells. Stimulation of DNA synthesis by low doses of serum in U-1242 MG cells is inhibited in a dose-responsive fashion by ganglioside GM1. However, serum itself counteracts the inhibitory effect of ganglioside in a dose responsive way. Kinetic analyses demonstrate that GM1 competes with some components of serum for sites on U-1242 MG cells (Kb of GM1 = 12.5 microM). On the other hand, GM1, GD1a, and GT1b stimulate DNA synthesis in quiescent U-1242 MG cells in both sparse and confluent conditions, indicating that ganglioside-stimulated DNA synthesis is dependent on the phase of cellular growth rather than cellular density. This growth stimulatory effect of gangliosides is more potent on quiescent, confluent cells than quiescent, sparse cells. These results demonstrate that exogenously added gangliosides can have opposite (bimodal) effects on progression of human glioma cells through the cell cycle depending upon the growth phase of the cells.

Cell Line↗
PubMed2006

Allogeneic acute rejection on fetal small-bowel graft: role of gangliosides.

In previous work, it was shown that gangliosides (Gang) have an inhibitory effect on lymphocyte proliferation as well as on delayed-type hypersensitivity response and mixed lymphocyte reaction. Therefore, we decided to examine the effect of gangliosides in acute allorejection after fetal intestinal transplantation. We used two female C57BL/6 mice on pregnancy day 19 as a source of fetal intestine. All animals were anesthetized with ketamine (70 mg/kg) and xylazine (10 mg/kg), intramuscularly. We harvested intestinal segments of 1 cm to transplant into BALB/c and C57BL/6 mice (male, weighing around 20 g) used as recipients. They were divided into groups of six animals each: isogeneic and allogeneic without treatment, or treated with tacrolimus 1 mg/kg/day, or gangliosides 3 and 9 mg/kg/day, during 7 days posttransplantation, intramuscularly. On postoperative day 7, intestinal grafts were collected and fixed in 10% formalin solution. Using an anesthetic overdose as euthanasia, we removed the intestinal grafts. Tissue samples were stained with hematoxylin-eosin for histological analysis regarding grafts development (D) and rejection (R) aspects. Data were analyzed by the Kruskal-Wallis test, considering P < or = 0.05 as significant. In the isogeneic and tacrolimus groups, we observed a very good degree of development (D = 9 +/- 0.5; D = 9 +/- 0.4, respectively), but a severe degree of rejection (R = 15 +/- 1.3) and a low degree of development (D = 1 +/- 0.8) in animals without treatment. The ganglioside groups showed D = 5 +/- 1.6 and R = 13 +/- 3.3, and D = 7 +/- 2.9 and R = 9 +/- 1.9, for the 3-mg and 9-mg groups, respectively. There was a statistically significant difference between the ganglioside groups and allogeneic groups without treatment. Based on the above data, we conclude that avascular fetal intestine transplantation is a good experimental model for studying immunological events, and that gangliosides only partially modulate the allorejection response, allowing intestinal development, mainly at the highest ganglioside dose. Maybe immunomodulation would be better observed by using isolated types of gangliosides or association with other immunosuppressive drugs.

Animals↗
PubMed1984

Adrenal medulla gangliosides.

The gangliosides were examined in adrenal glands of mouse, rat, guinea pig, rabbit, monkey, pig, ox and chicken. GM3 ganglioside was predominant in all examined animals except pig. In pig GD3 ganglioside was the major one. GM4 ganglioside was found in guinea pig and chicken. The distribution of sialic acid varied in each species. NeuNGly containing gangliosides were not detected in rat, guinea pig, rabbit and chicken. The other animals have both NeuNAc and NeuNGly containing gangliosides. Chromaffin granules from bovine adrenal medulla contain gangliosides at concentrations 3 and 7 times as great as microsomal and mitochondrial fractions, respectively. These gangliosides were NeuNAc-containing GM3 and NeuNGly containing GM3 in the same amount.

Adrenal Medulla↗
PubMed1991

Uptake and metabolism of radiolabelled GM1-ganglioside in skin fibroblasts from controls and patients with GM1-gangliosidosis.

The uptake and metabolism of [3-3H-sphingosine]GM1-ganglioside was measured in cultured skin fibroblasts from controls and patients with infantile, juvenile and adult GM1-gangliosidosis. When dissolved in medium with phosphatidylserine, GM1-ganglioside was efficiently taken up by cultured skin fibroblasts and transferred into lysosomes. A linear increase in GM1-ganglioside endocytosis was shown with phosphatidylserine concentrations of up to 40 micrograms/ml. A pulse-chase study revealed that [3H]GM1-ganglioside was metabolized to GM2-ganglioside, GM3-ganglioside, ceramide dihexoside, ceramide monohexoside, ceramide and sphingosine. Sphingosine was recycled to sphingomyelin. In a 20-h pulse study, cell lines from patients with GM1-gangliosidosis of infantile, juvenile and adult types hydrolysed 2-5%, 20-44% and 54-58% of the total endocytosed GM1-ganglioside respectively. These values were lower than in control cells (64.17 +/- 5.43% (n = 10]. The hydrolysis rates of exogenous [3H]GM1-ganglioside in cultured fibroblasts from patients with various types of GM1-gangliosidosis closely reflected the clinical severity.

Cells, Cultured↗
PubMed1979

A comparison of the ganglioside distributions of fat tissues in various animals by two-dimensional thin layer chromatography.

The ganglioside distributions of various fat tissues from human, rabbit, rat, mouse, chicken and frog were compared with pig adipose gangliosides by two-dimensional thin layer chromatography. It was found that there is a remarkable species variation in ganglioside distribution, especially in the composition and relative concentration of complex gangliosides. Differing from pig adipose tissues, those of human, rabbit, rat, mouse, chicken, but not frog, contained GM3 as a most abundant ganglioside. The data for human, rabbit and chicken indicated a simple distribution of only NeuAc-type gangliosides, while those for rat and mouse indicated a rather complicated pattern containing both NeuAc- and NeuGc-type gangliosides. The ganglioside pattern of the frog fat body differed markedly from those of mammalian fat tissues because of the presence of three different, unusual monosialosylgangliosides as major components. In other respects, a substantial amount of disialosylgangliosides was commonly found in all animal fat tissues.

Adipose Tissue↗
PubMed1989

Gangliosides in the brain in adult Down's syndrome and Alzheimer's disease.

Quantitative analysis of total gangliosides and of ganglioside composition by HPTLC has been carried out on the gray matter of frontal cerebral cortex of six brains from Down's syndrome (DS) adults, six age-matched controls, six Alzheimer's disease (AD) adults, and six controls matched for age with the AD brains, as well as on three DS and six control cerebellum specimens. In addition, the analyses were carried out on specimens of corpus callosum of five adult DS and five control brains. No abnormalities were found in the gangliosides of DS corpus callosum. In DS frontal cortex, the concentration of total gangliosides was reduced, and there was a decrease in the fraction of GT1b and GD1b, and an increase in those of GT1a, GD3, GM1 and GM2; the ratio of total b-series to a-series gangliosides was decreased. Very similar abnormalities were found in the gangliosides of DS cerebellum. In AD frontal cortex, by contrast, the total gangliosides and their composition were normal by comparison with age-matched controls, with the minor exception of reductions in the fractions of GQ1b and GT1L. It is concluded that abnormalities in gangliosides exist in the brain in DS that are unrelated to AD-type pathology and may reflect developmental disturbances.

Aged↗
PubMed1994

Ganglioside content of rat liver after administration of ethanol and pentazocine or sucrose supplemented diets.

In a previous paper, we determined the effect of either ethanol or pentazocine administered separately on the ganglioside content of rat liver. In the present paper we have investigated the effect of pentazocine injection on the liver ganglioside contents of chronic alcoholic rats. The effect of high carbohydrate ingestion was also studied. Thirty male Wistar rats were divided into three experimental groups that received ethanol and pentazocine, a carbohydrate supplemented diet or a laboratory diet and water. Liver ganglioside contents were slightly increased in the ethanol plus pentazocine group as compared to the control and high carbohydrate diet groups. No differences were found between the two latter groups. The percentage distribution of individual gangliosides (ganglioside pattern) was also modified. A decrease in gangliosides belonging to the b-series (GD3, GD1b, GT1b and GQ1b) in parallel with an increase in that of the a-series (GM2, GM1 and GD1a) were found for both the ethanol plus pentazocine and the high-carbohydrate fed rats. The results suggest that ethanol or high carbohydrate ingestion diminishes the activity of GD3 synthase, a key enzyme in the metabolism of gangliosides, which determines the proportion of gangliosides, belonging to the a- and b-series.

Animals↗