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PubMed1996

Age-related changes of the ganglioside long-chain base composition in rat cerebellum.

The ganglioside mixture from the cerebellum of young, 6 month old and two years old rats, was fractionated by reversed phase high performance liquid chromatography, each ganglioside homogeneous in the oligosaccharide chain as well as in the long-chain base being subsequently quantified. Two long-chain bases, LCB, were components of the five major gangliosides GM1, GD1a, GD1b, GT1b and GQ1b, these being the C18:1 LCB and C20:1 LCB. The content of C20:1 ganglioside molecular species was lower than that of the C18:1 one. In very young animals, day 8, the C20:1 ganglioside species represented about 8% of the total ganglioside content, then they progressively increased and reached, at 2 years, about 42% of the total. C18:1 GD1a and C18:1 GT1b, were the major species in young animals and reached their highest content at day 29, being 1.45 and 1.28 nmol/mg protein, respectively. The content of these two species decreased in adult and old animals and at two years it was 0.71 and 0.82 nmol/mg protein, respectively.

Aging↗
PubMed1982

Murine leukemia. Proposed role for gangliosides in immune suppression.

Glycolipid-bound sialic acid levels were elevated 2 to 4-fold in the sera of two strains of mice bearing thymic lymphoma produced either spontaneously (AKR/J) or due to chemical carcinogenesis [Swiss mice injected with 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboximide]. The serum glycolipid-bound sialic acid level reflected the tumor burden of the AKR/J mice during the early stages of leukemogenesis. Furthermore, the elevation was found to coincide with the ontogenesis of thymic lymphoma and not to be simply an age-dependent phenomenon. TLC analysis of Florisil column-purified gangliosides from the sera of AKR/J and Swiss mice suggested presence of gangliosides with mobilities very close to GM2 and GM3 standards respectively. On the premise that the elevated glycolipid levels in circulation might interfere with normal lymphocyte functions, the immunoinhibitory properties of exogenously added mixed gangliosides were examined on tests of in vitro correlates of the immune response. Gangliosides inhibited concanavalin A and lipopolysaccharide-induced [3H]-thymidine, [14C]-leucine and [3H]-lysine uptake by normal AKR/J mouse thymocytes and spleen cells. Mixed gangliosides also suppressed the two-way mixed lymphocyte reaction of AKR/J X Swiss and AKR/J X DBA/2 spleen cells. These and other results strongly suggest a general immunologically relevant role for gangliosides in the ontogeny of thymic lymphoma of mice.

Animals↗
PubMed1986

Ganglioside-induced regeneration and reestablishment of axonal continuity in spinal cord-transected rats.

In this study we examined the effect of chronic GM-1 ganglioside treatment on the reestablishment of axonal continuity and functional recovery in spinal cord-transected rats. Previous studies have shown that chronic treatment with GM-1 ganglioside is effective in producing regeneration of lesioned mesostriatal dopaminergic neurons in the central nervous system [1, 2]. In addition, GM-1 ganglioside advances peripheral nerve regeneration following nerve crush injury [12]. Axonal continuity was determined by the ability of the spinal cord to transport horseradish peroxidase across the region of transection. Comparisons between ganglioside-treated and saline-treated controls showed that ganglioside treatment resulted in the reestablishment of axonal continuity between the spinal cord distal to the level of the transection and the brainstem. Saline-treated controls showed little evidence of axonal continuity between these two regions. Thus gangliosides induce reestablishment of axonal continuity and thereby could advance functional recovery in rats following spinal cord transection.

Animals↗
PubMed1988

Antibodies to ganglioside GM1 in patients with Alzheimer's disease.

Gangliosides are thought to have a role in neuronal development and regeneration while anti-ganglioside antibodies have been shown to impair these processes. In the present work we examined whether the neuronal degeneration in Alzheimer's disease is associated with the presence of anti-ganglioside antibodies. A significant level of antibodies specific to ganglioside GM1 but not to other gangliosides (GD1a, GD1b, GT1b and GQ1b) was found in patients with Alzheimer's disease as compared to normal age matched controls. A high level of antibodies to GM1 was also found in patients with multi-infarct dementia and Parkinson's disease with dementia but not in non-demented patients with other neurodegenerative diseases. These results may reflect a specific change in ganglioside metabolism which is associated with the neurodegenerative processes underlying Alzheimer's disease and other causes of dementia.

Adult↗
PubMed1982

The topography of gangliosides in the membrane of the chromaffin granule of bovine adrenal medulla.

We have studied the topography of the gangliosides of the adrenal chromaffin granules by using neuraminidase to remove sialic acid from membrane gangliosides of intact and ruptured chromaffin granules. Residual sialic acid was then measured to compare the availability of gangliosides on the outer and inner surfaces of the membrane. Measurement of protein sialic acid served as a control since these residues are known to be on the inner surface of the membrane. Prolonged digestion of broken membranes showed that maximally 75% of both lipid and protein-bound sialic acid residues are available to neuraminidase. Prolonged digestion of intact granules produced no measureable loss of sialic acid from either protein or lipid fractions. Comparison of the thin-layer chromatograms of gangliosides extracted from digested and undigested membranes showed no preferential digestion of any component. We conclude that at least 75% of the gangliosides are on the inner leaflet of the membrane and suggest that all of the gangliosides are so located.

Adrenal Medulla↗
PubMedDate not supplied

Acute alcohol decreases gangliosides in mouse brain.

We have reported that single doses of alcohol diminish total sialic acid in rat brain. Recent results indicate that this effect seems to be largely accounted for by alcohol-induced reduction in gangliosides. In these experiments, five replicate groups of mice were injected IP with a single dose of 20% alcohol and saline as control. At 1 hour postinjection, alcohol decreased total brain gangliosides (p less than 0.03) at 1 and 2 g/kg, but not at 3, 4, and 6 g/kg. Free whole-brain sialic acid was increased by 2 g/kg alcohol, which is consistent with the observed decrement in gangliosides at this dose. However, activity of sialidase on the endogenous substrates was not greatly affected by 2 g/kg of alcohol, indicating that ganglioside decrement is probably not attributable to activation of the catabolic enzyme. These results confirm and extend our earlier reports that incriminated gangliosides in the acute action of alcohol. The data also raise the possibility that the effect is due to the "excitatory," rather than the depressive actions of alcohol. Moreover, the action may involve an increased hydrolysis of membrane gangliosides by sialidase.

Animals↗
PubMed1996

The effect of exogenous gangliosides on matrix metalloproteinase secretion by human glioma cells in vitro.

Matrix metalloproteinases (MMPs) are zinc-dependent peptidases and are amongst those enzymes responsible for extracellular matrix (ECM) degradation during tumour-cell migration. Gangliosides are a family of acidic membrane glycolipids thought to play a role during cell development, differentiation and oncogenic transformation. In this descriptive study, we investigated the effects of six exogenous gangliosides (GM1, GM3, GD1a, GD1b, GD3 and GT1b) on the secretion of MMP-2 (72 kDa gelatinase or gelatinase-A) and MMP-9 (92 kDa gelatinase or gelatinase-B). Cell-conditioned media from eight human glioma-derived cell-lines served as the source of MMPs and were investigated using SDS-PAGE zymography. Six of the cell lines showed upregulation of secretion of both enzymes by all six gangliosides. Of the remaining two cell lines, one showed inhibition of MMP secretion by all gangliosides and the other had a small but differential response to the range of gangliosides investigated. These results suggest that gangliosides may stimulate glioma cell invasiveness by promoting MMP expression.

Collagenases↗
PubMed2005

Oxygenation alters ganglioside expression in rat liver following partial hepatectomy.

Gangliosides from livers of weanling rats were analyzed after 15% partial hepatectomy (PH) and different pre- and post-operative hyberbaric oxygenation (pre- and postHBO). Neu5Ac was the predominant ganglioside-derived sialic acid (>85%) compared to Neu5Gc. Almost identical low total sialic acid content (Neu5Ac+Neu5Gc) of the control and operated nonHBO animals opposed a 6.4- to 7.6-fold increase in pre- and postHBO animals (69.26 and 81.64pmol/mg wet weight, respectively). NanoESI-QTOF mass spectrometry combined with HPTLC immunostaining revealed GM3(Neu5Ac) and GM3(Neu5Gc) as major gangliosides, correlating with the respective sialic acid concentrations. Minor neolacto-series gangliosides were enhanced in preHBO and postHBO, but GM1-core gangliosides only in preHBO rats. GM2 and GalNAc-GM1b were clearly detectable in oxygenated rats compared to traces in the control and nonHBO animals. These results point at a functional role of gangliosides in liver growth regulation and reconstitution after PH combined with pre- and post-operative HBO treatment.

Animals↗
PubMed2004

Gangliosides and N-glycoproteins function as Newcastle disease virus receptors.

The interaction of enveloped viruses with cell surface receptors is the first step in the viral cycle and an important determinant of viral host range. Although it is established that the paramyxovirus Newcastle Disease Virus binds to sialic acid-containing glycoconjugates the exact nature of the receptors has not yet been determined. Accordingly, here we attempted to characterize the cellular receptors for Newcastle disease virus. Treatment of cells with tunicamycin, an inhibitor of protein N-glycosylation, blocked fusion and infectivity, while the inhibitor of O-glycosylation benzyl-N-acetyl-alpha-D-galactosamide had no effect. Additionally, the inhibitor of glycolipid biosynthesis 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol blocked viral fusion and infectivity. These results suggest that N-linked glycoproteins and glycolipids would be involved in viral entry but not O-linked glycoproteins. The ganglioside content of COS-7 cells was analyzed showing that GD1a was the major ganglioside component; the presence of GM1, GM2 and GM3 was also established. In a thin-layer chromatographic binding assay, we analyzed the binding of the virus to different gangliosides, detecting the interaction with monosialogangliosides such as GM3, GM2 and GM1; disialogangliosides such as GD1a and GD1b, and trisialogangliosides such as GT1b. Unlike with other viruses, our results seem to point to the absence of a specific pattern of gangliosides that interact with Newcastle disease virus. In conclusion, our results suggest that Newcastle disease virus requires different sialic acid-containing compounds, gangliosides and glycoproteins for entry into the target cell. We propose that gangliosides would act as primary receptors while N-linked glycoproteins would function as the second receptor critical for viral entry.

Animals↗
PubMed2005

G(M1)-ganglioside degradation and biosynthesis in human and murine G(M1)-gangliosidosis.

BACKGROUND: Gangliosides are building blocks of cell membranes and their biosynthesis and degradation have been extensively studied in the past. Regulation of the metabolism of these glycolipids controls fundamental cell functions. G(M1)-gangliosidosis, a neurodegenerative glycosphingolipid storage disease, is caused by deficiency of lysosomal beta-galactosidase with consequent disruption of the normal degradative pathway of G(M1)-ganglioside. We studied the impact of G(M1)-ganglioside accumulation on its biosynthetic enzyme in cells and tissues from human patients and from the G(M1)-gangliosidosis mouse model. METHODS: We tested the qualitative and quantitative pattern of gangliosides by thin layer chromatography and N-acetylneuraminic acid dosage, respectively. Regulation of G(M1)-ganglioside biosynthesis was evaluated by G(M1) synthase assay in human and murine samples. RESULTS: G(M1)-ganglioside accumulation has an inhibitory effect on the human but not on the mouse G(M1) synthase. We present evidence that G(M1) synthase activity in human and murine cells are regulated by different mechanisms. CONCLUSIONS: Alternative pathways in the mouse may account for these results and possibly explain some of the phenotypical differences between the human and mouse forms of this disorder.

Animals↗
PubMed2006

Analysis of human hippocampus gangliosides by fully-automated chip-based nanoelectrospray tandem mass spectrometry.

Modern microfluidic devices are currently introduced in electrospray (ESI) mass spectrometry (MS), tending to substitute the classical capillary-based ESI infusion. Automated systems using the combination of robotized sample handling and chip-based ESI are significantly increasing the analysis reproducibility, precision, throughput, and efficiency. In the last couple of years our group developed the chip-based ESI-MS approach for glycomics in biomedical research and applied it for oligosaccharide, glycopeptide and ganglioside investigation. Here we report upon the optimization and application of this modern technique for the analysis of differential ganglioside expression patterns in human fetal and adult hippocampus. By this methodology, ganglioside species exhibiting high degree of heterogeneity in the ceramide motifs and biologically-relevant modifications could be identified in human hippocampus. The ultra-high reproducibility of the experiments uniquely provided by the chip-ESI approach allowed for a reliable MS-based ganglioside comparative assay. Moreover, the particular feature of chip ESI-tandem MS to provide structural information at high sensitivity was useful for detailed characterization of hippocampus-associated species. The experimental data presented in this study indicate the benefits of microfluidic/MS for determination of the topospecific brain ganglioside composition and development-related changes in their expression, which might be of high value in clinical investigation and for studies related to ganglioside-based therapy of central nervous system diseases.

Adult↗
PubMed2004

Secondary accumulation of gangliosides in lysosomal storage disorders.

Glycosphingolipids (GSLs) known as gangliosides have been documented to accumulate in a wide range of lysosomal storage disorders, including those with and without primary defects in ganglioside degradation. The same two gangliosides, GM2 and GM3, are often found elevated in diseased neurons whereas in normal mature neurons both are essentially undetectable. Altered expression of these two gangliosides does not appear to result solely from cellularity changes or gliosis since immunocytochemical studies show that both GM2 and GM3 reside in vesicular structures within affected neurons. Elevated expression of one of these gangliosides (GM2) has also been found to closely correlate with the growth of ectopic dendrites on susceptible neurons, a phenomenon that uniquely characterizes many lysosomal diseases. Understanding the precise role of the endosomal-lysosomal system in the overall homeostatic control of GSL expression in neurons can be expected to provide key insight into both the function of gangliosides and the pathogenic mechanisms underlying lysosomal disease.

Gangliosides↗
PubMed2003

Ganglioside GT1B and melatonin inhibit brain mitochondrial DNA damage and seizures induced by kainic acid in mice.

The effects of ganglioside GT1b or melatonin on damage to brain mitochondrial DNA (mtDNA) and seizures induced by kainic acid were investigated both in vivo and in vitro. An intraperitoneal (i.p.) injection of kainic acid (45 mg/kg) produced broad-spectrum limbic and severe sustained seizures in all of the treated mice. These seizures were completely abolished by an intracerebroventricular (i.c.v.) injection of ganglioside GT1b (90 nmol/brain), a potent inhibitor of glutamate receptor mediated activation and translocation of protein kinase C and lipid peroxidation, or an i.p. injection of melatonin (20 mg/kg), a potent scavenger of hydroxyl radicals (*OH). The administration of kainic acid caused damage to mtDNA in brain frontal and central portion of cortex in mice. The damage to mtDNA was abolished by pre-injection of ganglioside GT1b (90 nmol/brain, i.c.v.) or melatonin (20 mg/kg, i.p.). In vitro exposure of kainic acid (0.25, 0.5 or 1.0 mM) inflicted damage to mtDNA in a concentration-dependent manner. The damage to mtDNA induced by 1.0 mM kainic acid was attenuated by the co-treatment with 60 microM ganglioside GT1b or 1.5 mM melatonin. Furthermore, kainic acid (0.5 or 1.0 mM) increased lipid peroxidation in a concentration-dependent manner when incubated with a homogenate prepared from mice brain at 37 degrees C for 20 or 60 min. However, the increased lipid peroxidation was completely abolished by the co-treatment with ganglioside GT1b (60 microM) or melatonin (1.5 mM). These results suggest that reactive oxygen species including hydroxyl radical (*OH) may play a role in the damage to brain mtDNA and seizures induced by kainic acid. We conclude that the preventive effect of melatonin or ganglioside GT1b against kainic acid-induced mtDNA damage or seizures may be due to its scavenging of reactive oxygen species including the *OH.

Animals↗
PubMed2002

Synthesis and selectin-binding activity of N-deacetylsialyl Lewis X ganglioside.

A novel analogue of sialyl Lewis X ganglioside, N-deacetylsialyl Lewis X ganglioside, was synthesized. Methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-5-trifluoroacetamido-D-glycero-alpha-D-galacto-2-nonulopyranosylonate-(2 --> 3)-2,4,6-tri-O-benzoyl-D-galactopyranosyl trichloroacetimidate was coupled with 2-(trimethylsilyl)ethyl [2-acetamido-6-O-benzyl-2-deoxy-3-O-(4-methoxybenzyl)-beta-D-glucopyranosyl]-(1 --> 3)-[2,4,6-tri-O-benzyl-beta-D-galactopyranosyl]-(1 --> 4)-2,3,6-tri-O-benzyl-beta-D-galactopyranoside to give the desired pentasaccharide in high yield. The glycosylation of the pentasaccharide acceptor, which was derived from its precursor by removal of the 3-methoxybenzyl group, with the phenyl 1-thioglycoside derivative of L-fucose using N-iodosuccinimide-trifluoromethanesulfonic acid as promoter, produced the hexasaccharide. Proper manipulation of the protecting groups of the hexasaccharide afforded the corresponding glycosyl imidate, which was coupled with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol. Selective reduction of the azido group, N-acylation with octadecanoic acid, and the complete removal of the protecting groups gave the desired N-deacetylsialyl Lewis X ganglioside. L-Selectin bound more strongly to N-deacetylsialyl Lewis X ganglioside than to the sialyl Lewis X ganglioside, whereas E- and P-selectins bound equally well to the two gangliosides.

E-Selectin↗
PubMed2002

Ganglioside GD1a impedes lipopolysaccharide-induced maturation of human dendritic cells.

Immunosuppressive membrane gangliosides are released by tumor cells and inhibit normal antigen presenting cell (APC) function. To better understand this process, we have studied the effect of gangliosides on lipopolysaccharide (LPS)-induced maturation of human dendritic cells (DCs). Immature DCs were generated in vitro from human peripheral blood monocytes and were exposed for 72 h to a highly purified ganglioside, G(D1a). During the last 24 h, LPS was added to effect maturation. As assessed by fluorescence activated cell sorting (FACS) analysis, incubation in 50 microM G(D1a) significantly blunted the LPS-induced maturation of the dendritic cells. The expected up-regulation of expression of the co-stimulatory molecules CD80 and CD86 was ablated and that of CD40 was reduced, as were surface CD83 expression and intracellular CD208 production. In addition, ganglioside pretreatment of DC markedly inhibited the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake characteristic of LPS-activated DC. Furthermore, ganglioside-exposed DC also evidenced a broad down-regulation of the cytokine release that is normally initiated by LPS exposure, i.e., there was no increase in IL-1 beta, IL-6, IL-10, IL-12, or tumor necrosis factor (TNF)-alpha release. That a common mechanism may underlie these defects was suggested by the finding that G(D1a) exposure of DC also inhibited the nuclear binding of NF-kappa B that is normally induced by LPS. These results suggest that tumor gangliosides may blunt the anti-tumor immune response in vivo by binding and interfering with dendritic cell maturation.

Antigens, CD↗
PubMed2003

A synthetic ceramide analog ameliorates spatial cognition deficit and stimulates biosynthesis of brain gangliosides in rats with cerebral ischemia.

A synthetic ceramide analog, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) upregulates ganglioside biosynthesis in several cell lines. In cultured cortical neurons, neurotrophic effects of L-PDMP on neurite outgrowth and synaptic activity were demonstrated. In addition, it was found that L-PDMP could ameliorate the spatial cognition deficit in rats with ischemia. To elucidate this effect, we evaluated the effect of L-PDMP on brain ganglioside biosynthesis and its therapeutic efficacy against spatial cognition deficit in rats made ischemic. Rats were trained for 2 weeks, using an 8-arm radial maze task, and then forebrain ischemia was induced. L-PDMP was injected i.p. at 40 mg/kg twice a day starting from day 1 or 3 after ischemia induction for 6 or 4 days, respectively. The first study showed significantly reduced spatial cognition deficit at 12 h after the final drug administration, and L-PDMP tended to attenuate apoptosis in hippocampal CA1. To examine the effect of L-PDMP on brain ganglioside biosynthesis, N-[3H]acetyl-D-mannosamine was infused into the lateral ventricle via an injection cannula at 12 h after the final drug administration. After 4 h, the brain gangliosides were purified and analyzed. Upregulation of ganglioside biosynthesis by L-PDMP was observed on days 3 and 5 after ischemia. These results are an indication that L-PDMP may ameliorate spatial cognition deficit by upregulating ganglioside biosynthesis in ischemic brain.

Animals↗
PubMed2006

Modulation of growth factor signaling by gangliosides: positive or negative?

Increasing evidence has implicated gangliosides, sialic acid-containing cell surface glycosphingolipids, in the biological and clinical behavior of many types of human tumors. Gangliosides are overexpressed and actively shed by tumor cells, can bind to normal cells in the tumor microenvironment, and have a number of biological properties that could conceivably alter tumor-host interactions to influence the survival of the malignant cells that carry these molecules. One major area of investigation is the modulation of cell signaling by gangliosides. Published studies have demonstrated modulation of growth factor signaling through the epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), Trk family, and insulin receptors. Studies conducted over the past 10 y have demonstrated either inhibition or enhancement of signaling by gangliosides, depending on cell type, ganglioside species, and experimental conditions. Of particular concern are conflicting studies that demonstrate opposite effects of gangliosides on the same growth factor receptor. This chapter discusses a methodological approach to addressing this apparent conflict.

Carbohydrate Sequence↗
PubMed2001

Comparison of ganglioside profiles in nuclei and whole cells of NG108-15 and NG-CR72 lines: changes in response to different neuritogenic stimuli.

The plasma and nuclear membranes of neural cells have been shown to express gangliosides to a limited extent before, and at increasing levels during, differentiation. Recent studies employing qualitative cytochemistry have shown that GM1 expression in particular is significantly elevated in both membranes by specific neuritogenic agents. The present study provides a more complete description of ganglioside patterns of the 2 membranes of NG108-15 cells and a mutated form of the latter lacking gangliotetraose gangliosides. Nuclei of wild type NG108-15 cells were found to contain predominantly GM1 and GD1a, whereas whole cells had those in addition to substantial amounts of GM2 and GM3. GM1 and GD1a levels increased 2--3.5-fold in both whole cells and nuclei following axonogenic stimulation, but changed little in response to dendritogenic agents. GM2 expression, limited to the plasma membrane, showed little if any change with axonogenic stimuli but a 1.5--2-fold increase following treatment with dendritogenic agents. GM3 resembled GM2 in being virtually absent from the nuclear membrane, while its presence in the plasma membrane showed only modest change at most with any of the stimuli. The gangliotetraose ganglioside-deficient mutant cell line, NG-CR72, had significantly higher basal levels of GM2 in the plasma membrane compared to wild type NG108-15 cells, and this level increased significantly on treatment with dendritogenic agents. Basal GM3 levels were greatly reduced in the mutant cells and changed little with any of the stimuli. As expected, nuclei of NG-CR72 cells were virtually devoid of gangliosides. These mutant cells were previously shown to extend well defined dendritic neurites but were incapable of forming stable axonal processes. This study thus demonstrates major differences in the ganglioside content of wild type and mutated NG108-15 cells and their nuclei, and in their response to different neuritogenic stimuli.

Animals↗