Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson's disease models.

Current treatments for Parkinson's disease (PD) provide only symptomatic relief, with no disease-modifying therapies identified to date. Repurposing FDA-approved drugs to treat PD could significantly shorten the time needed for and reduce the costs of drug development compared with conventional approaches. We developed an efficient strategy to screen for modulators of ß-glucocerebrosidase (GCase), a lysosomal enzyme that exhibits decreased activity in patients with PD, leading to accumulation of the substrate glucosylceramide and oxidized dopamine and α-synuclein, which contribute to PD pathogenesis. Using a GCase fluorescent probe and affinity-based fluorescence polarization assay, we screened 1280 structurally diverse, bioactive, and cell-permeable FDA-approved drugs and found that the antipsychotic quetiapine bound GCase with high affinity. Moreover, quetiapine treatment of induced pluripotent stem cell-derived (iPSC-derived) dopaminergic neurons from patients carrying mutations in GBA1 or LRRK2 led to increased wild-type GCase protein levels and activity and partially lowered accumulation of oxidized dopamine, glucosylceramide, and α-synuclein. Similarly, quetiapine led to activation of wild-type GCase and reduction of α-synuclein in a GBA mutant mouse model (Gba1D409V/+ mice). Together, these results suggest that repurposing quetiapine as a modulator of GCase may be beneficial for patients with PD exhibiting decreased GCase activity.

Anti-allergic property of 4,8-sphingadienine stereoisomers in vivo and in vitro model.

4,8-Sphingadienines (SD), metabolites of glucosylceramides (GlcCer), are sometimes determined as key mediators of the biological activity of dietary GlcCer, and cis/trans geometries of 4,8-SD have been reported to affect its activity. Since regulating excessive activation of mast cells seems an important way to ameliorate allergic diseases, this study was focused on cis/trans stereoisomeric-dependent inhibitory effects of 4,8-SD on mast cell activation. Degranulation of RBL-2H3 was inhibited by treatment of 4-cis-8-trans- and 4-cis-8-cis-SD, and their intradermal administrations ameliorated ear edema in passive cutaneous anaphylaxis reaction, but 4-trans-8-trans- and 4-trans-8-cis-SD did not. Although the activation of mast cells depends on the bound IgE contents, those stereoisomers did not affect IgE contents on RBL-2H3 cells after the sensitization of anti-TNP IgE. These results indicated that 4-cis-8-trans- and 4-cis-8-cis-SD directly inhibit the activation of mast cells. In conclusion, it was assumed that 4,8-SD stereoisomers with cis double bond at C4-position shows anti-allergic activity by inhibiting downstream pathway after activation by the binding of IgE to mast cells.

Does tamoxifen have a therapeutic role outside of breast cancer? A systematic review of the evidence.

INTRODUCTION: Tamoxifen is a widely used hormonal based therapy for breast cancer in the adjuvant and metastatic setting, prolonging overall and recurrence-free survival. There has been increasing interest in the potential for novel "off-target" effects of tamoxifen and its metabolite N-desmethyltamoxifen across a number of cancer types. We aim to review the current literature regarding the potential use of tamoxifen in other primary malignancies. METHOD: A qualitative systematic review was performed according to the PRISMA guidelines using pre-set search criteria across the PubMed, Cochrane and Scopus databases from 1985 to 2019. Additional results were generated from included papers references. RESULTS: A total of 324 papers were identified, of which 47 were included; a further 29 articles were obtained from additional referencing to give a total of 76 articles. Clinical trials have demonstrated benefits with the use of tamoxifen in isolation and combination, specifically in patients with advanced non-resectable malignancy, however results are not consistent across the literature. In vivo data consistently suggests that off target effects of tamoxifen are mediated through the ceramide pathway or through inhibition of protein kinase C (PKC). CONCLUSIONS: With increased focus upon the potential of repurposing drugs, tamoxifen may be a candidate for repurposing in the wider cancer setting. There is evidence to suggest that the ceramide or PKC pathway could act as a therapeutic target for tamoxifen or alternative chemotherapeutics and merits further investigation.

A chemical genetic screen reveals that iminosugar inhibitors of plant glucosylceramide synthase inhibit root growth in Arabidopsis and cereals.

Iminosugars are carbohydrate mimics that are useful as molecular probes to dissect metabolism in plants. To analyse the effects of iminosugar derivatives on germination and seedling growth, we screened a library of 390 N-substituted iminosugar analogues against Arabidopsis and the small cereal Eragrostis tef (Tef). The most potent compound identified in both systems, N-5-(adamantane-1-yl-ethoxy)pentyl- L-ido-deoxynojirimycin (L-ido-AEP-DNJ), inhibited root growth in agar plate assays by 92% and 96% in Arabidopsis and Tef respectively, at 10 µM concentration. Phenocopying the effect of L-ido-AEP-DNJ with the commercial inhibitor (PDMP) implicated glucosylceramide synthase as the target responsible for root growth inhibition. L-ido-AEP-DNJ was twenty-fold more potent than PDMP. Liquid chromatography-mass spectrometry (LC-MS) analysis of ceramide:glucosylceramide ratios in inhibitor-treated Arabidopsis seedlings showed a decrease in the relative quantity of the latter, confirming that glucosylceramide synthesis is perturbed in inhibitor-treated plants. Bioinformatic analysis of glucosylceramide synthase indicates gene conservation across higher plants. Previous T-DNA insertional inactivation of glucosylceramide synthase in Arabidopsis caused seedling lethality, indicating a role in growth and development. The compounds identified herein represent chemical alternatives that can overcome issues caused by genetic intervention. These inhibitors offer the potential to dissect the roles of glucosylceramides in polyploid crop species.

Augmentation of dietary glucosylceramide hydrolysis by the novel bacterium Glucerabacter canisensis NATH-2371T.

The purpose of this study was to evaluate the effects of intragastrical administration of Glucerabacter canisensis NATH-2371T on glucosylceramide (GluCer) digestion in mice. Although G. canisensis was unable to utilize starch and cellulose, coculture of G. canisensis with mouse fecal bacteria greatly increased GluCer hydrolysis in polysaccharide medium, indicating that G. canisensis grew in competition with other intestinal bacteria. Although most of the administered G. canisensis cells were detected in feces, some cells were present in the colorectum contents, which had GluCer-hydrolyzing activity. These results indicate that G. canisensis can viably transit through the mouse gut. Administration of G. canisensis to mice fed diets supplemented with GluCer or GluCer-containing foods significantly enhanced GluCer hydrolysis. Since G. canisensis did not show acute toxicity, it may be useful as a probiotic to augment GluCer hydrolysis in the large intestine. Abbreviations: GluCer: glucosylceramide; KPi: potassium phosphate buffer; C-M: chloroform-methanol.

Glucerabacter canisensis gen. nov., sp. nov., isolated from dog feces and its effect on the hydrolysis of plant glucosylceramide in the intestine of dogs.

A Gram-positive, obligately anaerobic, oval-rod shaped, non-spore-forming, and non-pigmented bacterium, designated strain NATH-2371T (= JCM31739T = DSM105698T), was isolated from dog feces. Comparative 16S rRNA gene sequence analysis revealed that strain NATH-2371T belongs to Clostridium cluster XIVa, and the closest strains were Coprococcus comes ATCC 27758T (94.8% 16S rRNA gene sequence similarity) and Clostridium nexile DSM 1787T (94.0%). Strain NATH-2371T produced acetate, formate, and ethanol from glucose. Predominant cellular fatty acids are C16:0 and C16:0 DMA. On the basis of the phenotypic and genotypic differences, strain NATH-2371T represents a novel species in a new genus of the family Lachnospiraceae, for which the name Glucerabacter canisensis gen. nov., sp. nov., is proposed. This strain was found to efficiently hydrolyze plant glucosylceramide (GluCer). The abundance of strain NATH-2371T in dog feces was higher in young dogs than in old dogs. Incubation of dog fecal bacteria showed that GluCer-hydrolyzing activity decreased with the age of dogs. The cell number of strain NATH-2371T in dog feces appeared to be correlated with GluCer hydrolysis. Thus, this bacterium is likely to play a major role in GluCer hydrolysis in the dog intestine.

Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients.

BACKGROUND: We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT. METHODS: Seventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured. RESULTS: In patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89% (range 77-98), 88% (78-92) and 37% (29-46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73% (63-78), 54% (43-86), and 10% (3-18); decrease of glucosylsphingosine was 86% (78-93), 78% (65-91), 48% (46-50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment. CONCLUSIONS: Our explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.

Defective Self-Renewal and Differentiation of GBA-Deficient Neural Stem Cells Can Be Restored By Macrophage Colony-Stimulating Factor.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme glucosylceramidase (GCase). Deficiency in GCase leads to characteristic visceral pathology and lethal neurological manifestations in some patients. Investigations into neurogenesis have suggested that neurodegenerative disorders, such as GD, could be overcome or at least ameliorated by the generation of new neurons. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are potential candidates for use in the treatment of neurodegenerative disorders because of their ability to promote neurogenesis. Our objective was to examine the mechanism of neurogenesis by BM-MSCs in GD. We found that neural stem cells (NSCs) derived from a neuronopathic GD model exhibited decreased ability for self-renewal and neuronal differentiation. Co-culture of GBA-deficient NSCs with BM-MSCs resulted in an enhanced capacity for self-renewal, and an increased ability for differentiation into neurons or oligodendrocytes. Enhanced proliferation and neuronal differentiation of GBA-deficient NSCs was associated with elevated release of macrophage colony-stimulating factor (M-CSF) from BM-MSCs. Our findings suggest that soluble M-CSF derived from BM-MSCs can modulate GBA-deficient NSCs, resulting in their improved proliferation and neuronal differentiation.

Anti-apoptotic and Beneficial Metabolic Activities of Resveratrol in Type II Gaucher Disease.

Gaucher disease (GD) is one of the most common lysosomal storage disorders and is caused by an inherited deficiency in glucocerebrosidase. Resveratrol is a phytoalexin that has many beneficial activities, including anti-oxidant, anti-apoptotic, and neuroprotective effects. The aim of this study was to determine if resveratrol has a therapeutic effect on primary fibroblast cells derived from a patient with type II GD. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of resveratrol on cell viability. The expression patterns of apoptosis-inducing factor (AIF), Bcl-2-associated X protein (Bax), caspase-3, acetyl-coenzyme A acetyltransferase 1 (ACAT1), E3-binding protein (E3BP), and citrate synthase (CS) were evaluated by Western blotting to characterize the effect of resveratrol treatment on GD cells. TLC was performed to determine glucosylceramide levels in resveratrol-treated GD cells. Resveratrol increased GD cell viability compared to untreated control cells. Further, resveratrol treatment dose-dependently decreased the apoptotic factors AIF, Bax, and cleaved caspase-3 levels, whereas ACAT1, E3BP, and CS expression dose-dependently increased. TLC analysis showed reduced levels of intracellular glucosylceramides in resveratrol-treated GD cells. These findings demonstrate that resveratrol can reduce cellular stress resulting from glucosylceramide accumulation, and suggest that resveratrol should be studied further as a novel therapeutic agent for GD.

Therapeutic Potential of Resveratrol in Type I Gaucher Disease.

Resveratrol is a natural polyphenol that possesses various beneficial properties, such as anti-inflammatory, anti-oxidant, and neuroprotective effects. This study evaluated the potential therapeutic effects of resveratrol on primary fibroblasts derived from a patient with Gaucher disease. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were carried out to determine whether resveratrol affects cell survival. Changes in the expression levels of apoptosis-inducing factor (AIF), Bax, cleaved caspase-3, acetyl-coenzyme A acetyltransferase 1 (ACAT1), E3-binding protein (E3BP), and citrate synthase (CS) were determined by western immunoblot to characterize the effect of resveratrol treatment on Gaucher disease cells. Intracellular glucosylceramide levels in resveratrol-treated patient cells were determined by thin-layer chromatography (TLC). Resveratrol significantly increased the viability of patient cells in comparison with that of control cells. After exposure to resveratrol, expression levels of the apoptotic factors AIF, Bax, and cleaved caspase-3 dose-dependently decreased, while those of ACAT1, E3BP, and CS dose-dependently increased. TLC showed a significant decrease in glucosylceramide levels in patient cells treated with resveratrol. These findings demonstrate that resveratrol can reduce apoptotic events and glucosylceramide levels in Gaucher disease cells, and that it merits further research as a possible therapeutic compound.

Bioactives of Artemisia dracunculus L. enhance insulin sensitivity by modulation of ceramide metabolism in rat skeletal muscle cells.

OBJECTIVE: An increase in ectopic lipids in peripheral tissues has been implicated in attenuating insulin action. The botanical extract of Artemisia dracunculus L. (PMI 5011) improves insulin action, yet the precise mechanism is unknown. The aim of this study was to determine whether the mechanism by which the bioactive compounds in PMI 5011 improve insulin signaling is through regulation of ceramide metabolism. METHODS: L6 Myotubes were separately preincubated with 250 µM palmitic acid with or without PMI 5011 or four bioactive compounds isolated from PMI 5011 and postulated to be responsible for the effect. The effects on insulin signaling, ceramide, and glucosylceramide profiles were determined. RESULTS: Treatment of L6 myotubes with palmitic acid resulted in increased levels of total ceramides and glucosylceramides, and cell surface expression of gangliosides. Palmitic acid also inhibited insulin-stimulated phosphorylation of protein kinase B/Akt and reduced glycogen accumulation. Bioactives from PMI 5011 had no effect on ceramide formation but one active compound (DMC-2) and its synthetic analog significantly reduced glucosylceramide accumulation and increased insulin sensitivity via restoration of Akt phosphorylation. CONCLUSIONS: The observations suggest that insulin sensitization by PMI 5011 is partly mediated through moderation of glycosphingolipid accumulation.

Gromwell (Lithospermum erythrorhizon) supplementation enhances epidermal levels of ceramides, glucosylceramides, ß-glucocerebrosidase, and acidic sphingomyelinase in NC/Nga mice.

We have previously reported that dietary gromwell (Lithospermum erythrorhizon; LE) prevents the development of atopic dermatitis (AD) with increased epidermal levels of total ceramide (Cer), the major lipid maintaining epidermal barrier. In this study, we investigated whether the increased level of total Cer induced by dietary LE would be related to the altered metabolism of glucosylceramide (GlcCer) and sphingomyelin (SM), two major precursor lipids in Cer generation. NC/Nga mice, an animal model of AD, were fed a control diet (group CA: atopic control) or a diet with 70% ethanol LE extracts (1% in diet; group LE) for 10 weeks. Individual species of Cer, GlcCer, and SM were analyzed by high-performance thin layer chromatography. In the epidermis of group CA, total Cer (including Cer2 and Cer5-7) and total GlcCer (including GlcCer-B/C/D) were significantly reduced; these levels in group LE were increased to levels similar to the normal control group of BALB/c mice (group C). In addition, protein expressions and activities of ß-glucocerebrosidase (ß-GlcCer'ase) and acidic sphingomyelinase (aSMase), enzymes for GlcCer or SM hydrolysis, respectively, were increased in group LE. However, alterations of Cer1, Cer3/4, GlcCer-A, and all SM species (including SM1-3) were not significant among groups C, CA, and LE. Dietary gromwell increases GlcCer-B/C/D, and further enhances the generation of Cer2 and Cer5-7 with high protein expressions and activities of ß-GlcCer'ase and aSMase.

Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain.

Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate. However, the extended use of eliglustat and related compounds for the treatment of glycosphingolipid storage diseases with CNS manifestations is limited by the lack of brain penetration of this drug. Property modeling around the D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP) pharmacophore was employed in a search for compounds of comparable activity against the GCS but lacking P-glycoprotein (MDR1) recognition. Modifications of the carboxamide N-acyl group were made to lower total polar surface area and rotatable bond number. Compounds were screened for inhibition of GCS in crude enzyme and whole cell assays and for MDR1 substrate recognition. One analog, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide (CCG-203586), was identified that inhibited GCS at low nanomolar concentrations with little to no apparent recognition by MDR1. Intraperitoneal administration of this compound to mice for 3 days resulted in a significant dose dependent decrease in brain glucosylceramide content, an effect not seen in mice dosed in parallel with eliglustat tartrate.

The pathophysiology of GD - current understanding and rationale for existing and emerging therapeutic approaches.

Gaucher disease is a genetic disorder of sphingolipid metabolism resulting from dysfunction of the lysosomal membrane-associated glycoprotein glucocerebrosidase (GBA) and resulting in intracellular accumulation of glucosylceramide and other glycolipids. Although the gene defect and relevant biochemical pathways have been defined, the mechanisms by which substrate accumulation causes disease manifestations are not well understood. The direct effects of a build up of substrate laden cells may account for some aspects of disease but the overall pathology is likely to be more complex with effects of stored material on a variety of intra and extra cellular functions. In this article we review the GBA gene and its protein product, with associated defects, lipid metabolism and storage, enzyme misfolding and endoplasmic reticulum stress, calcium homeostasis, oxidative stress and autophagy and at each point examine how therapies that are currently available, in clinical development or at earlier stages of basic research might address the pathological mechanisms.

Determination of glucosylceramide contents in crop tissues and by-products from their processing.

Glucosylceramides were surveyed in crop tissues and by-products from their processing. Apple pulp contained the highest amount (0.94 mg g(-1)) of glucosylceramide and relatively less sterylglucoside, which is the major contaminant of partially purified glucosylceramide. Glucosylceramide from apple pulp was principally composed of 2-hydroxypalmitic acid as the fatty acid, 4-hydroxy-cis-8-sphingenine as the sphingoid base, and glucose as the hexose, similar to those of commercial preparations isolated from rice bran or wheat germ. Apple pulp may be an alternative source for the commercial production of glucosylceramides.

Down-regulation of Bcl-2 in the fetal brain of the Gaucher disease mouse model: a possible role in the neuronal loss.

Gaucher disease is a lysosomal storage disorder resulting from an inborn deficiency of glucocerebrosidase. To investigate the genes responsible for the neuronal symptoms of Gaucher disease, gene expression profiles were analyzed in brains of the Gaucher disease mouse model using a cDNA microarray, and it was found that the bcl-2 gene is down-regulated. Immunoblotting and apoptosis assay were performed to study the relationship between the decreased expression of Bcl-2 and neuronal death on the brains of Gaucher mice fetuses at embryonic day 17.5 (E17.5) and E19.5. Decreased expression of Bcl-2 was observed in the brain stem and cerebellum but not in cortex by immunoblotting. In situ labeling of DNA fragmentation using terminal transferase-mediated dUTP nick-end-labeling (TUNEL) assay confirmed that apoptosis occurred in the brain stem and cerebellum. More apoptotic cells were detected in the brains of Gaucher mice fetuses at E19.5 than at E17.5. These results suggest that the accumulation of either glucocerebroside or glucosylsphingosine, as a result of glucocerebrosidase deficiency, affects gene expression and could be responsible for neuronal cell death.

Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis.

Paediatric neurodegenerative diseases are frequently caused by inborn errors in glycosphingolipid (GSL) catabolism and are collectively termed the glycosphingolipidoses. GSL catabolism occurs in the lysosome and a defect in an enzyme involved in GSL degradation leads to the lysosomal storage of its substrate(s). GSLs are abundantly expressed in the central nervous system (CNS) and the disorders frequently have a progressive neurodegenerative course. Our understanding of pathogenesis in these diseases is incomplete and currently few options exist for therapy. In this review we discuss how mouse models of these disorders are providing insights into pathogenesis and also leading to progress in evaluating experimental therapies.

Glycosphingolipids modulate renal phosphate transport in potassium deficiency.

BACKGROUND: Potassium (K) deficiency (KD) and/or hypokalemia have been associated with disturbances of phosphate metabolism. The purpose of the present study was to determine the cellular mechanisms that mediate the impairment of renal proximal tubular Na/Pi cotransport in a model of K deficiency in the rat. METHODS: K deficiency in the rat was achieved by feeding rats a K-deficient diet for seven days, which resulted in a marked decrease in serum and tissue K content. RESULTS: K deficiency resulted in a marked increase in urinary Pi excretion and a decrease in the V(max) of brush-border membrane (BBM) Na/Pi cotransport activity (1943 +/- 95 in control vs. 1184 +/- 99 pmol/5 sec/mg BBM protein in K deficiency, P < 0.02). Surprisingly, the decrease in Na/Pi cotransport activity was associated with increases in the abundance of type I (NaPi-1), and type II (NaPi-2) and type III (Glvr-1) Na/Pi protein. The decrease in Na/Pi transport was associated with significant alterations in BBM lipid composition, including increases in sphingomyelin, glucosylceramide, and ganglioside GM3 content and a decrease in BBM lipid fluidity. Inhibition of glucosylceramide synthesis resulted in increases in BBM Na/Pi cotransport activity in control and K-deficient rats. The resultant Na/Pi cotransport activity in K-deficient rats was the same as in control rats (1148 +/- 52 in control + PDMP vs. 1152 +/- 61 pmol/5 sec/mg BBM protein in K deficiency + PDMP). These changes in transport activity occurred independent of further changes in BBM NaPi-2 protein or renal cortical NaPi-2 mRNA abundance. CONCLUSION: K deficiency in the rat causes inhibition of renal Na/Pi cotransport activity by post-translational mechanisms that are mediated in part through alterations in glucosylceramide content and membrane lipid dynamics.

Undernutrition decreases serine palmitoyltransferase activity in developing rat hypothalamus.

BACKGROUND/AIMS: Undernutrition reduces the hypothalamic ganglioside concentration. This may be attributed to some modifications in the contents of precursors of sphingolipid biosynthesis in undernourished rats. The present study evaluated the serine palmitoyl transferase activity (SPT; EC 2.3.1.50) during the development of the rat hypothalamus. This work also shows the L-[3-(14)C]serine metabolic labeling of hypothalamic sphingolipids in normal and undernourished rats at weaning. METHODS: The SPT activity was determined in microsomal fractions obtained from the hypothalamus of normal rats (diet: 25% protein) and pre- and postnatally undernourished rats (diet: 8% protein since pregnancy) at 21 days of gestational age and at 7, 14, and 21 days of postnatal life. RESULTS: The enzymatic activity was lower in the hypothalamus of undernourished than in the hypothalamus of control rats since the 7th postnatal day. Incorporation of the precursor L-[3-(14)C]serine into sphingolipid fraction was lower in the hypothalamus of undernourished rats than in the hypothalamus of control rats on the 21st postnatal day which coincided with the age of the highest difference in SPT activity between normal and undernourished rats. CONCLUSION: These results indicate that undernutrition reduces the biosynthesis of the main sphingolipids during the period of brain growth spurt.