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PubMed1990

Age-dependent changes in monkey lenticular gangliosides.

The content, composition, and distribution of gangliosides were examined in the lenses of normal rhesus monkeys aged 6-16 years. Gangliosides were isolated by organic solvent extraction. DEAE-Sephadex ion-exchange column chromatography, and thin-layer chromatography (TLC). Ganglioside contents determined by the thiobarbituric acid method increased in the lens with aging. TLC analysis of gangliosides showed a much more complex pattern with aging, and the predominant gangliosides were tentatively identified as GM3, GM1, and GD1a. Individual lenticular gangliosides were identified by TLC-immunostaining procedures using anti-GM1 and anti-asialoGM1 antisera.

Aging↗
PubMed1990

Impaired nerve regeneration in streptozotocin-diabetic rats is improved by treatment with gangliosides.

The rate of sciatic nerve regeneration and the effect of ganglioside treatment thereon were studied in the streptozotocin-diabetic rat. Two experimental protocols were used. In the first, sciatic nerves were crushed at 3 weeks of diabetes and treatment with purified bovine brain gangliosides (10 mg/kg/day ip) was begun the day before crush. In the second, nerves were crushed at 5 weeks of diabetes and treatment was started 7 days before crush. Regeneration was evaluated in both cases with the pinch-reflex test at different time points after crush. In either situation untreated diabetic rats showed a decreased rate of regeneration when compared to untreated nondiabetic rats, with a more severe reduction in 5-week diabetic rats. Ganglioside treatment improved regeneration in the second protocol; untreated diabetic rats had regenerated 10.6 +/- 0.9 mm (mean +/- SEM) at 7 days postcrush, while nerves from ganglioside-treated and control rats had regenerated 16.4 +/- 1.1 and 20.3 +/- 1.0 mm, respectively (n = 9-11, P less than 0.001 for untreated vs ganglioside-treated diabetics with two-way ANOVA). Ganglioside treatment did not alter the rate of regeneration in nondiabetic rats.

Animals↗
PubMed1985

Sialosyllactotetraosylceramide, a novel ganglioside antigen detected in human carcinomas by a monoclonal antibody.

A novel ganglioside was detected in a small cell lung carcinoma by TLC-immunostaining of gangliosides with a monoclonal antibody, the C-50 MAb. Structural characterization showed this ganglioside to be IV3NeuAc-LcOse4Cer, a hitherto unknown ganglioside. This ganglioside has also been detected as a minor component in many different carcinomas using the C-50 MAb. The normally dominant CA-50 ganglioside antigen is IV3NeuAc, III4Fuc-LcOse4Cer. Based upon solid-phase binding to IV3NeuAc, III4-LcOse4Cer and IV3NeuAc-LcOse4Cer it is concluded that the C-50 MAb recognizes an epitope present in sialylated type I carbohydrate chains.

Aged↗
PubMed1987

Gangliosides stimulate dome formation in cultured canine kidney epithelial cell line (MDCK).

The effect of exogenous gangliosides on the occurrence of domes in MDCK cell cultures was investigated in view of the involvement of both dome formation and gangliosides in cell growth, differentiation and transepithelial transport. Dome formation was increased by gangliosides in medium free of fetal calf serum. Among the gangliosides tested, GM3 and GD3 isolated from porcine kidney were most active, increasing the dome number 12-17-fold. Since gangliosides from kidney were more active than those from brain and erythrocytes, the hydrophobic moiety as well as sialic acid might be involved in this activity. These results indicate that tissue-specific molecules of gangliosides function as inducers or mediators of dome formation. The mechanism probably involves adenylate-cyclase or another transmembrane biosignal-transducing system.

Animals↗
PubMed1996

Intercellular transfer of shed tumor cell gangliosides.

Three distinct steps underlie immumosuppression by tumor gangliosides: (i) their shedding by the tumor cell, (ii) binding to target leukocytes in the tumor microenvironment, and (iii) action upon the target cell. While shedding is well documented, cell to cell transfer of shed gangliosides is not. To address this, we employed a dual chamber culture system. In this system, metabolically radiolabeled lymphoma cells shed gangliosides into the conditioned medium of the contralateral chamber, which contained normal fibroblasts as the target cell. The shed lymphoma cell gangliosides bound avidly to the target fibroblasts in a trypsin-resistant manner (1-2 x 10(6) and 7 x 10(6) molecules/fibroblast in 24 and 48 h). Significantly higher than binding rates of purified lymphoma gangliosides added exogenously, these binding rates in a system which models the in vivo microenvironment suggest that cell to cell ganglioside transfer is a highly efficient process.

Animals↗
PubMed1996

Antigen binding of antiganglioside antibodies in vitro is strongly influenced by the ganglioside composition of the sample.

The ability of antiganglioside antibodies to detect their respective antigens in various environments was studied. In contrast to sensitive detection of pure ganglioside standards by ELISA, antibody binding to mixtures of gangliosides was drastically reduced. This loss of sensitivity also occurred with immunostaining of gangliosides absorbed to silica gel. Moreover, absorption of antibodies to antigen-containing lipid vesicles failed, if the vesicles were prepared together with other gangliosides. These data indicate that antigen accessibility is strongly influenced by surrounding gangliosides. This should be considered whenever gangliosides are traced by antibodies. The ELISA procedure appears useful to test for such properties.

Animals↗
PubMed1978

Ganglioside alterations in guinea pig brains at end stages of experimental Creutzfeldt-Jakob disease.

Gangliosides were isolated from guinea pig brains at the end stages of experimental Creutzfeldt-Jakob disease. Quantitative analyses revealed marked decreases of ganglioside levels in pathologically devastated tissues such as cerebral cortex (-21%), basal ganglia and thalamus (-18%), and brain stem (-23%). The cerebellum revealed only minor pathological abnormalities and its ganglioside level remained unchanged. Thin-layer chromatography of the Creutzfeldt-Jakob brain gangliosides showed aberrant ganglioside patterns in all regions studied, including the cerebellum. With some exceptions, a trend in ganglioside pattern changes was detected which consisted of proliferation of GM3, GD3, GD2 and loss of GM1, GD1a, GD1b and GT1b.

Animals↗
PubMed1982

Elevated ganglioside concentration in serum and peripheral blood lymphocytes from multiple sclerosis patients in remission.

The ganglioside concentration in pooled serum from 20 patients with clinically definite multiple sclerosis (MS) was determined and compared with that in pooled serum from a similar number of healthy blood donors. There as a significant increase in the concentration of ganglioside-bound sialic acid from 691 +/- 57 micrograms/100 ml in the control sera to 926 +/-m 83 micrograms 100 ml in MS patients' sera. The profile of individual gangliosides in the two groups was identical, the four main structures being GM3, GD3, and GD1a and GT1b. The ganglioside pattern and concentration in peripheral blood lymphocytes derived from MS patients and controls was identical with the predominant GM3, and small proportions of Gd3. MS lymphocytes also showed a 39% increase in ganglioside content over control lymphocytes. The implication of such pronounced ganglioside increases is discussed with regard to the impaired immunocompetence of lymphocytes reported in MS.

Adult↗
PubMed1983

Cellular hypersensitivity to gangliosides and myelin basic protein in multiple sclerosis.

Peripheral blood lymphocytes from patients with multiple sclerosis (MS), other neurological diseases and healthy controls were investigated for the presence of cell-mediated hypersensitivity to brain gangliosides and myelin basic protein using an active E-rosette assay. Sensitivity to myelin basic protein and gangliosides was found in MS patients in acute relapse and with progressive disease, whereas no sensitivity was found in MS patients in remission. Patients with other neurological diseases showed no response to gangliosides, but sensitization to myelin basic protein was found in a patient with leucoencephalopathy and in 4 of 6 stroke patients. Healthy controls did not respond to either antigen. In MS patients a positive correlation was seen between lymphocyte responses to myelin basic protein and to gangliosides. The data suggest that in comparison to gangliosides, myelin basic protein is a weaker stimulator of active rosette-forming cells. Moreover, cellular hypersensitivity to myelin basic protein is not MS-specific and may be present as a consequence of brain damage. However, cellular hypersensitivity to gangliosides appears to be more specific to MS and may be important in the pathogenesis of the disease.

Animals↗
PubMed1989

Changes of mouse brain gangliosides during aging from young adult until senescence.

The brain gangliosides from young adult to senescent mice (BDF1 and C57BL/6) were studied. The total ganglioside concentrations of the whole brains were almost constant from young adulthood until the beginning of senescence, but decreased constant from young adulthood until the beginning of senescence, but decreased during senescence to about 80% of the constant level observed at the period before the beginning of senescence. In spite of the constancy of the ganglioside concentrations at the period before the beginning of senescence, the composition gradually changed, with an increase of GM1 and decreases of GD1b, GT1b and GQ1b. During the senescence, all of the gangliosides decreased in their concentrations, but GD1a, GT1b and GQ1b decreased to a markedly greater extent (GT1b greater than GD1a greater than GQ1b). The regional gangliosides in olfactory bulb, cerebrum cortex, cerebrum white matter, hippocampus, hypothalamus, cerebellum and medulla oblongata were compared between 3- and 30-month-old mice of both strains. Significant changes in ganglioside concentrations were observed in both strains in the cerebrum and the hippocampus. In the cerebrum white matter, cerebellum and medulla oblongata, GM1 and GM4 contents significantly increased in the senescent mice.

Aging↗
PubMed1996

Suppression of Theiler's murine encephalomyelitis virus induced demyelinating disease by administration of gangliosides.

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Gangliosides are membrane components of essentially all eukaryotic cells and are abundant in plasma membranes. Endogenous gangliosides have been implicated in cell recognition, cell adhesion, cell differentiation and neurite outgrowth. We studied the effect of gangliosides on TMEV-induced demyelinating disease (TMEV- IDD). We injected TMEV intracerebrally into susceptible SJL/J mice and induced TMEV-IDD. Gangliosides were injected subcutaneously and examined for various immunological indicators. The results show that when gangliosides were administered in the effector phase, TMEV-IDD was suppressed both clinically and histologically. Cellular immunity such as delayed-type hypersensitivity, and the proliferative response of T cells against TMEV and mitogens were decreased, and only in this group anti-TMEV IgG2a antibody was not detected. Taken together, these data suggest that administration of gangliosides suppressed the function of pathogenic Th1 cells and suppressed TMEV-IDD. Additionally, this study proposes the possibility of a new therapy in multiple sclerosis.

Animals↗
PubMed1992

Altered ganglioside composition in virally transformed rat embryo fibroblasts.

The composition of gangliosides was examined in a normal rat embryo fibroblast cell line (REF52) and in two viral transformants: a polyoma transformant (REF52-PyMLV) and a simian viral 40 transformant (REF52-SV40). The distribution of gangliosides in the cell lines was determined using gas-liquid chromatography and high-performance thin-layer chromatography. N-acetylneuraminic acid was the predominant sialic acid species detected in the three cell lines. The total ganglioside concentration (microgram/100 mg dry weight of cells) in the normal, PyMLV, and SV40 lines was 144.7 +/- 10.4, 153.8 +/- 9.2, and 86.1 +/- 6.8, respectively. Gangliosides GM3, GM2, GM1, and GD1a were the major species in the normal and transformed lines. The distribution of these gangliosides, however, differed markedly between the normal and the transformed lines and also between the transformed lines themselves. The transformed cells also differed from the normal cells in growth rate, morphology, and social behavior. The cell line with highest GM3 content (PyMLV) formed islands, whereas the normal and SV40 cell lines, which had lower GM3 levels, grew as monolayers. The findings suggest that PyMLV and SV40 transformation can have multiple and different effects on cellular ganglioside distribution and growth behavior.

Animals↗
PubMed1992

Enhancement of ganglioside GM3 synthesis in okadaic-acid-treated granulosa cells.

Okadaic acid is a potent inhibitor of type-2A (PP2A) and type-1 (PP1) protein phosphatases and has been proved to be a valuable tool for studies on the protein phosphorylation. We have investigated the effects of okadaic acid on rat granulosa cells in order to determine whether the regulation of ganglioside synthesis involves protein phosphorylation via inhibition of PP2A and PP1. Granulosa cells expressed luteinizing hormone (LH) receptors, measured as the binding of 125I-deglycosylated human chorionic gonadotropin (hCG) to intact cells, and synthesized the gangliosides NeuAc alpha 2-->3Gal beta 1-->4Glc beta 1-->1Cer (GM3) and Gal beta 1-->3GalNAc beta 1-->4[NeuAc alpha 2-->3]Gal beta 1-->4Glc beta 1-->1Cer (GM1), demonstrated by metabolic labeling of glycosphingolipids with [3H]galactose, in response to follicle-stimulating hormone (FSH). When FSH-stimulated granulosa cells were treated with 10 nM okadaic acid for 15 h, down-regulation of LH receptors, dissociation of LH receptor-effector coupling and significant decreases of intracellular and extracellular 3',5'-cyclic adenosine monophosphate (cAMP) levels were observed. The okadaic acid-induced desensitization to gonadotropin in granulosa cells was accompanied by increased ganglioside synthesis. The amount of 3H-labeled ganglioside GM3, the major ganglioside (about 95% of the total) synthesized by mature granulosa cells, was enhanced in okadaic acid-desensitized cells (to 215% of the control value) and in those desensitized by hCG (by 354%), forskolin (by 190%) and 12-O-tetradecanoylphorbol 13-acetate (by 143%). The results of this study suggest that an increase in the phosphorylation state of cells is accompanied by enhancement of ganglioside synthesis.

Animals↗
PubMed1991

Changes of endogenous ganglioside composition in mouse cerebrum primary cultures following long-term exposure to phorbol ester.

Changes in endogenous gangliosides caused by phorbol 12-myristate 13-acetate (PMA, 162 nM) were examined using mouse cerebrum primary cultures. The total ganglioside content was significantly decreased by 25% and 40% in PMA-treated cultures compared to control cultures on days 1 and 8, respectively. In addition, changes in the pattern of ganglioside composition were also observed in which the percentage of GM1 and GD3 in total gangliosides was significantly increased and, in contrast, the percentage of GD1a and GT1b was reduced. Treatment of neurons with PMA induced the change of morphology. These results suggest that the decrease in the total ganglioside content and changes in ganglioside composition produced by long-term exposure to PMA are related to the appearance of neuronal cell aggregation and neurite fasciculation.

Animals↗
PubMed1990

Polymorphic effects of exogenous gangliosides on antigen-induced lymphoproliferation and generation of MHC unrestricted cell mediated cytotoxicity.

Cell membrane gangliosides have been shown to be involved in a number of biological processes including cell adhesion, signal transduction and ligand receptor interactions. In this paper we analyzed the effects of a mixture of bovine brain gangliosides, currently in clinical use, on cell mediated immune responses in vitro. We show here that exogenous gangliosides inhibit mitogen and alloantigen induced lymphoproliferation. On the other hand effects on antigen induced blastogenesis were exquisitely dose dependent in that while high doses of gangliosides inhibited lymphoproliferation, probably by interfering in interleukin 2 receptor interactions, lower doses significantly enhanced antigen induced responsiveness. We also report that gangliosides inhibit the generation of lymphokine activated killer cells. Altogether, these data underline the immunoregulatory potential and the polymorphism of effects of exogenous gangliosides.

Cytotoxicity, Immunologic↗
PubMed1993

Variability in brain ganglioside content and composition of endothermic mammals, heterothermic hibernators and ectothermic fishes.

Content and composition of brain gangliosides were compared among endothermic mammals, heterothermic hibernators and ectothermic fishes from habitats with extreme ambient temperatures (tropic vs. antarctic waters). In general the content of brain gangliosides in fishes is significantly lower and exhibits a greater variability than in mammals. The composition of brain gangliosides was investigated using both one- and two-dimensional High Performance Thin Layer Chromatography (HPTLC). Both techniques showed a remarkable increase in the number of individual ganglioside fractions and an additional increase of higher polar fractions in fishes as compared with mammals. The 2D-HPTLC revealed a significant decrease in the relative proportion of alkali-labile gangliosides in the course of evolution from fish to mammals. Moreover this decrease in alkali-lability is correlated with the state of thermal adaptation (antarctic fishes, 53-66%; tropical cichlid fish, 35%). These results provide additional evidence for the notion that the extremely high polarity of brain gangliosides, especially of cold-blooded vertebrates, reflects a very efficient mechanism on the molecular level to keep the neuronal membrane functional under low temperature conditions.

Acclimatization↗
PubMed1995

Stimulation of cyclic adenosine 3',5'-monophosphate-dependent protein kinase with brain gangliosides.

The holoenzyme of cAMP-dependent protein kinase (cAMP-kinase) partially purified from the particulate fraction of rat brain was stimulated by gangliosides. Among various gangliosides tested, GM1 was most potent, giving Ka value of 19.5 microM. The maximal activation of the kinase was obtained with 100 microM GM1 using kemptide as substrate. Gangliosides inhibited the kinase activity of the catalytic subunit of cAMP-kinase. Of various substrates tested, the ganglioside-stimulated cAMP-kinase could phosphorylate microtubule-associated protein 2, synapsin I and myelin basic protein, but not histone H1 and casein. The molecular mechanisms of the stimulatory effect of gangliosides were investigated. The kinase activated with GM1 was inhibited by the addition of PKItide, a specific inhibitor for cAMP-kinase. However, GM1 did not dissociate the holoenzyme into the catalytic and regulatory subunits and did not interfere with the binding ability of cAMP to the holoenzyme. These results suggest that the gangliosides can directly activate cAMP-kinase in a different manner from cAMP.

Animals↗
PubMed1994

In vitro changes of ganglioside immunostain localization in developing neural cells.

The immunostains of GD3, c-pathway polysialogangliosides and gangliotetraosylgangliosides belonging to the a- and b-pathways were analyzed in embryo optic lobe cells. Cells were cultured in serum free media with, and without, bovine brain ganglioside mixture (largely gangliotetraosylgangliosides). Control cells differentiated in vitro, whereas ganglioside treated cells emitted almost no neurites. In immature cells, GD3 and c-gangliosides were extensively expressed and their immunostains were observed all over the cell (general localization), whereas gangliotetraosylgangliosides were scanty and their stain was preferentially restricted to discrete areas (in clusters). In control differentiated cells, the GD3 expression was strikingly reduced and its immunostain appeared in clusters; c-gangliosides were abundant and their stain was found with general localization; the expression of gangliotetraosylgangliosides became important and their stain was observed with general localization in most of the positive cells. In ganglioside treated cells, in spite of their undifferentiated morphology, the gangliotetraosylganglioside stain appeared with general localization. These results suggest that gangliosides involved in neural ontogenesis are preferentially located in clusters when they are scarce and have general localization when they are abundant in membranes.

Animals↗