Abstract— The developmental profiles of individual gangliosides of human brain were compared with those of rat brain. Interest was focused mainly on the pre‐ and early postnatal development. Human frontal lobe cortex covering the period from 10 foetal weeks to adult age and the cerebrum of rat from birth to 21 days were analysed. Lipid‐NANA and lipid‐P were followed; in the rat, also protein and brain weight. A limited number of samples of human cerebral white matter and cerebellar cortex were also studied. The following major results were obtained: The ganglioside concentration increased approximately three‐fold within a short period: in rat cerebrum, from birth to the 17th day; in human cerebral cortex, from the 15th foetal week to the age of about 6 months. The largest increase in the rat brain occurred by the 11th to the 13th day; in human brain by term. The relative increase of gangliosides during this period was more rapid than that of phospholipids. A hitherto unknown distinct early period of ganglioside and phospholipid formation in rat occurred by the second to fourth day. The changes in brain ganglioside pattern, characteristic of the developmental stages of the rat, were found to be equally pronounced in the human brain. Regional developmental differences in the ganglioside pattern were demonstrated in human brain. A characteristic white matter pattern, rich in monosialogangliosides, had developed by the age of 1 year. The increase in ganglioside concentration and the formation of the definitive ganglioside pattern of cerebellar cortex occurred later than in cerebral cortex. This cerebellar pattern was characterized by a very large trisialoganglioside fraction. The two periods of rapid ganglioside metabolism in rat brain preceded the two periods of rapid protein biosynthesis.

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Gangliosides and allied neutral glycosylceramides were isolated from human infant (2-24 months of age) cerebral cortex and white matter. The individual glycolipids were separated quantitatively by a combination of column and thin-layer chromatographic methods on silica gel, DEAE-cellulose and Sephadex G-25. In cerebral cortex G D 1 , and GM1 were the major fractions and constituted more than 70 per cent of the total gangliosides. The concentrations of neutral glycolipids, except for galactosylceramides, were very low: lactosylceramide and glucosylceramide comprised 30 and 5 nmol/g wet weight, respectively. In white matter their concentrations were 10 times higher. The ganglioside concentration was only 50 per cent of that in cerebral cortex: the difference was accounted for mainly by the much lower content of the major di-and trisialogangliosides.Stearic acid was the predominant fatty acid of all brain gangliosides. GM3 and G D 3 had a considerable content of the very long-chain fatty acids, Czz-C24, particularly in the white matter. Glucosylceramide and lactosylceramide had almost identical fatty acid patterns between each other in cerebral cortex and white matter. In the cerebral cortex stearic acid and in the white matter the very long-chain acids predominated. d20: 1 Sphingosine comprised more than 20 per cent of total sphingosine in all the gangliosides of the G1-and Gz-series. GM3 and GD3 like lactosylceramide contained significantly less of d20: 1 sphingosine. The findings suggest the existence of separate compartments for the biosynthesis of the gangliosides. Glucosylceramides and lactosylceramides of white matter have the same ceramide composition as the galactosylceramides with normal fatty acids and are thus unlikely to be intermediates in the metabolism of the major brain gangliosides which have a completely different fatty acid composition.A DETAILED determination of the ganglioside composition has only been performed on single human infant brains (SVENNERHOLM, 1963, 1967SUZUKI, 1965). In our recent study of a large number of foetal and infant brains (VANIER et al., 1971) only the four major gangliosides were determined and no data on other gangliosides were included. More detailed knowledge of the concentrations and compositions of the minor gangliosides and allied glycolipids is essential for a better understanding of the ganglioside metabolism in various types of cells and subcellular particles (HOLM et . KLENK (1942) originally identified stearic acid as the major fatty acid of brain gangliosides. TRAMS et al. (1962) reported the occurrence of minor amounts of 20:O and 22:O besides the predominating 18:O fatty acid, In many subsequent investigations stearic acid has been shown to be the predominating fatty acid of the total brain gangliosides fraction, but no systematic study is available on the fatty acid composition of the individual gangliosides in human brain. CISand C,,-sphingosines constituted approx. 90 per cent of the sphingosines of total human Present address: Fondation Gillet, Hapita...

Duodenal mucosal alkaline secretion increases in response to hydrochloric acid exposure. The tentative role of nitric oxide (NO) in the mediation of this response was investigated. The mucosal alkaline output by a duodenal segment was recorded by in situ titration in chloralose-anaesthetized rats. In some experiments the duodenal blood flow was estimated by laser-Doppler flowmetry. Exposure of the duodenum to acid (0.01 M HCl, 5 min) increased the alkaline secretion by approximately 85%. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1 intravenously or 0.3 mM intraluminally) blocked the secretory increment after mucosal acid exposure. Mean arterial pressure and basal alkaline secretion were markedly raised, whereas duodenal blood flow was decreased, when L-NAME was given intravenously (i.v.). Intraluminal (i.l.) administration left mean arterial pressure as well as duodenal blood flow unaltered, and the duodenal mucosal alkaline secretion was only slightly elevated. The stereoisomer NG-nitro-D-arginine methyl ester (D-NAME) had no effect on either basal or acid-induced duodenal alkaline output. In animals receiving L-arginine (10 mg kg-1 min-1 i.v., or 3 mM i.l.) and L-NAME, the acid exposure elicited an increase in duodenal mucosal alkaline secretion, similar to that observed in controls. The results suggest that the acid-induced increase in duodenal mucosal alkaline secretion involves NO synthesis, which takes place close to the lumen, probably within the mucosa.

Metabolic relationships between the four major brain gangliosides, GMI, GD1,, GDlb and GT1 were studied in oivu. Labelled acetate and glucosamine were injected intracerebrally into 6-12-day-old rats and the radioactivities of the cerebral gangliosides were analysed. Radioactivity from t3H]acetate was determined in sialic acid, sphingosine and stearic acid and from [l-14C]glucosamine in hexosamine and sialic acid. The gangliosides were labelled in proportion to their pool size. In 6day-old rats the labelling was approx. 30 per cent lower in the sialidase-stable sialyl group than in the labile one. When the brain gangliosides were labelled in 12-day-old rats, however, the specific activities of sialidase-labile and stable sialyl groups were the same at 0.5 months after the injection of precursors and disappeared at the same rate. The results indicate that at the age of 6 days a small pool of monosialogangliosides exists, which is converted to di-and trisialogangliosides. The degradation of gangliosides was studied by following the radioactivities in sphingosine and stearic acid from 2 to 6 months after the injection of labelled acetate. The specific activities of sphingosine and stearic acid decreased simultaneously at the same rate in all the four major gangliosides.The specific activity of stearic acid was the same in total brain lipids as in gangliosides.The half-lives for the degradation of the gangliosides were age-dependent and estimated to 60 days in adult rats. They were much shorter in younger rats but no reliable figures could be determined.A GREAT deal of progress has been made in the chemical identification of gangliosides, their distribution in the nervous system, subcellular localization and developmental changes (SVENNERHOLM, 1970). Much less is known about their metabolism. A stepwise addition of monosaccharide units to the appropriate giycolipid acceptor is the normal pathway of the biosynthesis of brain gangliosides (KAUFMAN, BASU and ROSEMAN, 1967) and the biodegradation proceeds, also stepwise, from the carbohydrate end (GATT, 1967;SVENNERHOLM, 1970). All the biosynthetic steps from ceramide to the major disialoganglioside GDla have been accounted for (KAUFMAN, BASU and ROSEMAN, 1968) but knowledge of the normal pathway for the formation of the other major disialoganglioside GDlb and the trisialoganglioside GT1 is still incomplete. Recently, ARCE, MACCIONI and CAPUTTO (1 971) produced experimental support for the assumption that GM1 is also the precursor for G,,,, which in turn is precursor for GTl. An interconversion between the four major brain gangliosides, GMl, GDi,, GDlb and GT1 with a liberation and addition of sialic acid seems plausible from the in v i m studies. Further support for this assumption is the subcellular enrichment of gangliosides, sialyltransferase and sialidase in the same subcellular fraction (SEMINARIO, HREN and GOMEZ, 1964;DEN and KAUFMAN, 1968;OHMAN, 1971).In previous in vivu studies, however, SUZUKI and KOREY (1964) showed that the specific activities of some carbohyd...