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PubMed1993

Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion.

A vascular thrombotic lesion localized to the rat sensorimotor cortex was produced following intravenous injection of the photosensitive dye rose bengal, and its activation with a small beam of high-intensity white light focused to the skull overlaying the sensorimotor cortex. In the sensorimotor cortex at various times after the triggering event, two contiguous brain regions with different degree(s) of neuronal damage can be distinguished: (1) a primary thrombotic ischemic core where the majority of cells are dead and (2) a penumbra region surrounding the core lesion in which a slower progressive neuronal degeneration is occurring. Importantly, in both brain regions the neuronal degeneration is associated with the activation and persistent translocation of protein kinase C (PKC) as indicated by an increase in 4-beta-3H-phorbol-12,13-dibutyrate (3H-PDBu) binding. Moreover, the demonstration that in the area penumbra the neuronal degeneration and the persistent translocation of PKC can be inhibited by a pretreatment with dizocilpine (i.e., MK-801) indicates that the dynamics of the progression of the neuronal degeneration are maintained by glutamate accumulating in the extraneuronal fluids. MK-801 additionally prevents the transcriptional activation of several immediate-early genes (IEGs) (e.g., c-fos) and their cognate third nuclear messenger (i.e., c-Fos) expression present in the hemisphere ipsilateral to the lesion. On the other hand, LIGA4 and LIGA20 derivatives of GM1 lysoganglioside reduce the membrane translocation of PKC and the neuronal damage in the penumbra area, but fail to change the increase of IEG expression in the cortex ipsilateral to the lesion.

Animals↗
PubMed1976

Sphingolipid base metabolism. Stereospecific uptake of proton in the enzymatic conversion of sphinganine 1-phosphate to ethanolamine 1-phosphate.

D-erythro-(2S, 3R)-Sphinganine 1-phosphate was incubated with rat liver microsomes in the presence of tritiated water. [3H]Ethanolamine 1-phosphate was isolated and converted, through a combination of enzymatic and chemical reactions, to [3H]glycine. The labeled glycine was incubated with D-amino acid oxidase, an enzyme which, in the catalysis of the conversion of glycine to glyoxylic acid, specifically removes the hydrogen in the S configuration at carbon atom 2 of glycine. Essentially complete retention of the labeled hydrogen occurred upon conversion to glyoxylic acid. The combined results indicate that the conversion of D-erythro-(2S,3R)-sphinganine 1-phosphate to palmitaldehyde and ethanolamine 1-phosphate, catalyzed by sphinganine-1-phosphate lyase of rat liver microsomes, proceeds with the stereospecific incorporation of 1 atom of solvent hydrogen into the R configuration of ethanolamine 1-phosphate.

Animals↗
PubMed1998

Role of sphingolipid-mediated cell death in neurodegenerative diseases.

The metazoan nervous system gives rise intradevelopmentally to many more neurons than ultimately survive in the adult. Such excess cells are eliminated through programmed cell death or apoptosis. As is true for cells of other lineages, neuronal survival is sustained by an array of growth factors, such that withdrawal of neurotrophic support results in apoptotic cell death. Apoptosis is therefore believed to represent a beneficial process essential to normal development of central and peripheral nervous system (CNS and PNS) structures. Although the initiation of neuronal apoptosis in response to numerous extracellular agents has been widely reported, the regulatory mechanisms underlying this mode of cell death remain incompletely understood. In recent years, the contribution of lipid-dependent signaling systems, such as the sphingomyelin pathway, to regulation of cell survival has received considerable attention, leading to the identification of lethal functions for the lipid effectors ceramide and sphingosine in both normal and pathophysiological conditions. Moreover, the apoptotic capacities of several cytotoxic receptor systems (e.g., CD120a, CD95) and many environmental stresses (e.g., ionizing radiation, heat-shock, oxidative stress) are now known to derive from the activation of multiple signaling cascades by ceramide or, under some circumstances, by sphingosine. Inappropriate initiation of apoptosis has been proposed to underlie the progressive neuronal attrition associated with various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders that are characterized by the gradual loss of specific populations of neurons. In such pathophysiological states, neuronal cell death can result in specific disorders of movement and diverse impairments of CNS and PNS function. In some autoimmune neurological diseases such as Guillain-Barré syndrome, demyelinating polyneuropathy, and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid-directed autoantibodies may lead to extensive cellular damages, resulting in increased permeability across brain-nerve barrier (BNB) and/or blood-brain barrier (BBB).

Animals↗
PubMed1998

Correlation between bioeffector characteristics of sphingolipids and the structure of their hydrophobic fragment.

The effect of the structure of the hydrocarbon sphingoid base chain (length, presence of double bonds, and steric configuration of functional groups) and the length of the fatty acid residue of a ceramide molecule on the bioregulatory activities of sphingoids and ceramides is reviewed. Particular emphasis is placed on the role of functional groups (OH- and NH2-) typical of the sphingoid chain.

Animals↗
PubMed2002

Developmental changes in the protein composition of sphingolipid- and cholesterol-enriched membrane domains of rat cerebellar granule cells.

The biological role of cell membrane domains has been investigated in a number of eukariotic cells, but less attention has been paid to the neuron. In the present investigation, we assessed the changes in lipid and protein composition of detergent-resistant membrane fractions prepared from cultured rat cerebellar granule cells, during differentiation and maturation in vitro. At any stage of the cell life, low-density, detergent-resistant fractions, characterised by the specific presence of prion protein, were enriched in glycolipids, cholesterol, and sphingomyelin. The enrichment in sphingomyelin was developmentally regulated, increasing continuously during cell differentiation and maturation. Concerning proteins, domains were enriched in Fyn and TAG-1, which present exclusively within this fraction at any stage of cell culture, and in GAP-43, mainly during the differentiation stage. On the other side, proteins affecting signal transduction and cytoskeleton-related proteins (heterotrimeric G-proteins, protein kinase C, MARCKS, tubulin), were not enriched within detergent-resistant fractions during cell differentiation, but were recovered within this fraction in mature neurons. These results indicate that during different cellular life stages, specific proteins are recruited within detergent-resistant membrane domains of the neuron and suggest their involvement in specific physiological phenomena (differentiation, maturation and/or aging).

Animals↗
PubMed1995

Effects of intravenous fumonisin B1 in rabbits: nephrotoxicity and sphingolipid alterations.

Fumonisin B1 is hepatotoxic in all species, but nephrotoxicity has only been reported in rats. It is a specific inhibitor of sphinganine N-acyltransferase. Our objective was to determine the target organs for fumonisin toxicosis in the rabbit. We administered fumonisin B1 ( > 95% pure) intravenously to adult rabbits and examined selected clinical, biochemical, and histological parameters for up to 5 days. In a pilot study, rabbits were given fumonisin B1 at 1, 0.5, 0.3, 0.15, or 0 mg/kg daily for 4 or 5 days and then euthanized. Additional rabbits were given a single dose of fumonisin B1 at 1 mg/kg and euthanized on day 2 or 4. In the formal time-course study, rabbits were given a single dose of fumonisin B1 at 0 or 1.25 mg/kg and euthanized on days 1, 3, or 5. Rabbits given multiple doses of fumonisin B1 were lethargic and anorectic, and had decreased urine production. Liver- and renal-associated clinical chemistry parameters were elevated. Renal lesions consisted of severe proximal tubular necrosis. Liver lesions were variable and consisted of mild necrosis, hepatocyte vacuolation, and bile stasis. The sphinganine-to-sphingosine ratio, in both target and nontarget tissues, was markedly elevated in treated rabbits. A single dose of fumonisin B1 induced renal but not hepatic injury. Therefore, the target organs for fumonisin B1 toxicity in rabbits are kidney and liver, with the kidney being more sensitive.

Animals↗
PubMed1996

Studies of the action of ceramide-like substances (D- and L-PDMP) on sphingolipid glycosyltransferases and purified lactosylceramide synthase.

We have studied the effects of D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) and its L-enantiomer on glycosphingolipids in cultured normal human kidney proximal tubular cells. We found that D-PDMP exerted a concentration-dependent reduction in the metabolic labelling and cellular levels of glucosylceramide (GlcCer), lactosylceramide (LacCer), and the globo-series glycosphingolipids, GbOSe3Cer and GbOse4Cer. It also directly inhibited the activity of UDP-glucose:ceramide beta 1--> 4-glucosyltransferase (GlcT-1) and UDP-galactose: GlcCer beta 1-->4 galactosyltransferase (GalT-2). In contrast, L-PDMP had opposite effects on the metabolic labelling of GlcCer, LacCer, and GbOse3Cer. The levels of GlcCer and LacCer were increased, while the labelling and level of GbOse4Cer were strongly reduced. Purified GalT-2 from human kidney was inhibited by D-PDMP and stimulated by L-PDMP. It appears likely that the different glycosphingolipid glycosyltransferases possess similar binding sites for the ceramide moiety, which are blocked by binding to D-PDMP and, in the case of GbOse4Cer synthase, by L-PDMP as well. The stimulatory effects of L-PDMP on GlcCer and LacCer synthases may be the result of binding to a modulatory site on the glycosyltransferases; in intact cells, the enzyme-analog complex may afford protection against the normal catabolic inactivation of the enzymes.

Carbohydrate Conformation↗