bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleotide Sugars, Nucleotide Sulfate, and ATP Transporters of the Endoplasmic Reticulum and Golgi Apparatusa,
Authors: BERNINSONE PATRICIA , HIRSCHBERG CARLOS B.
Published: February 2006

Abstract: The lumina of the endoplasmic reticulum and Golgi apparatus are the subcellular sites where glycosylation, sulfation, and phosphorylation of secretory and membrane‐bound proteins, proteoglycans, and lipids occur. Nucleotide sugars, nucleotide sulfate, and ATP are substrates in the above reactions and must first be translocated from the cytosol into the lumen of these organelles. Translocation of these nucleotide derivatives is mediated by highly specific transporters, which are antiporters with the corresponding nucleoside monophosphate, as shown by genetic and biochemical approaches in mammals and yeast. Studies with mammalian, yeast, and protozoa mutants have shown that a defect in a specific translocator results in selective impairments of glycosylation of proteins, lipids and proteoglycans in vivo. Several of these transporters have been purified, cloned, and found to encode very hydrophobic proteins with multitransmembrane domains. Experiments with yeast and mammalian cells demonstrate that these transporters play a regulatory role in posttranslational modifications.
Development of Salivary Gland Cell Lines for Studies of Signaling and Physiologya,
Authors: SOLTOFF STEPHEN P. , GRUBMAN SHELLEY A. , JEFFERSON DOUGLAS M.
Published: February 2006

We developed and characterized an immortalized rat parotid cell line to use in salivary gland studies. The cells were immortalized by retroviral transduction of SV40 large T antigen into isolated parotid cells. Using immunocytochemical techniques, we found that the immortalized epithelial cells were ductal, rather than acinar, in nature. Cells were grown under coculture conditions with lethally irradiated NIH3T3 cells. One cell line, which was designated RPG1/SV40 cells (for rat parotid gland 1/SV40 transformant), was selected for characterization. These cells formed a sheet epithelium with tight junctions and a measurable transepithelial resistance. RPG1/SV40 cells responded to muscarinic receptor (carbachol) and/or P2 purinoceptor (ATP and UTP) stimuli with increases in the following: (1) intracellular free‐calcium concentration ([Ca2+]i); (2) the short‐circuit current (ISC) across the epithelium; (3) the tyrosine phosphorylation of PKCδ; and (4) MAP kinase activity. Thus, the cells appear to be useful for a wide range of studies involving physiology, biochemistry, and signal transduction approaches.
Transcriptional Regulation of Salivary Proline‐rich Protein Gene Expressiona
Authors: ANN DAVID K. , LIN H. HELEN
Published: February 2006

Abstract: Mechanisms governing gene expression and regulation in eukaryotes are remarkably complex. The results from in vivo transgenic and in vitro transfection studies designed to identify cis‐element(s) and trans‐factor(s) associated with the salivary proline‐rich proteins (PRPs) gene expression are utilized as a paradigm to discuss the regulation of salivary‐specific gene expression. Particular attention is given to the molecular mechanism(s) underlying the salivary PRP R15 gene regulation. In rodents, the PRPs are selectively expressed in the acinar cells of salivary glands, and are inducible by the β‐agonist isoproterenol as well as by dietary tannins. The results from a series of experiments using chimeric reporter constructs containing different lengths of the R15 distal enhancer region, their mutations, and various expressing constructs are analyzed and discussed. These data suggest that the inducible nuclear orphan receptor NGFI‐B may participate in the regulation of salivary acinar cell‐specific and inducible expression of the rat R15 gene via three distinct distal NGFI‐B sites. Taken together, a model for the induction of R15 gene expression by isoproterenol is proposed. However, the exact molecular basis of this NGFI‐B‐mediated transactivation of cAMP‐regulated R15 expression remains to be established.
Protein Secretion by Rat Parotid Acinar Cells: Pathways and Regulation
Authors: CASTLE J. DAVID
Published: February 2006

Abstract: Protein secretion from rat parotid acinar cells occurs in both the absence and presence of secretory agonists. Release takes place by four pathways that are distinguished by combined examination of their timing following biosynthetic labeling, their relative composition of salivary proteins, and their sensitivity to secretagogue stimulation. Following pulse‐labeling with a radioactive amino acid, two unstimulated export pathways are detected‐a constitutive‐like pathway that is coupled to maturation of secretory granules and the later unstimulated exocytosis of secretory granules. In both cases, protein release is insensitive to secretory antagonists. Two regulated secretory pathways are also detected. The major regulated pathway comprises stimulated exocytosis of secretory granules and requires application of β‐adrenergic agonists (≥ 1 μM). A newly discovered minor regulated pathway resembles the constitutive‐like pathway in secretory composition but requires low‐dose stimulation by either β‐adrenergic or cholinergic agonists. The latter pathway may provide a significant component of basal secretion by the parotid gland during periods between meals.
Salivary Abnormalities in Prader‐Willi Syndrome
Authors: HARTA P. SUZANNE
Published: February 2006

Abstract: Prader‐Willi syndrome (PWS) is characterized by psychomotor and growth retardation, infantile hypotonia, characteristic facies, small hands and feet, dental abnormalities, and early onset of childhood hyperphagia with consequent obesity. PWS is associated with abnormalities of chromosome 15. Approximately 75% of patients have a deletion of 15q11q13 on the paternal homologue, whereas 20–25% have inherited both chromosome 15s from the mother and none from the father, a condition known as maternal uniparental disomy (UPD). Thus, it is a lack of paternal alleles in the 15q11q13 region that results in PWS. Thick, sticky saliva is a consistent finding in patients with PWS. We have characterized salivary flow and composition in individuals with PWS. Salivary flow in patients with PWS is approximately 20% of that in controls. In addition, the salivary ions and proteins are present in increased amounts, possibly reflecting a concentration effect relative to decreased water in the saliva. Both deletion and uniparental disomy patients exhibit these findings, suggesting that the gene(s) involved are subject to imprinting.
Antigen Processing and Autoimmunity: Evaluation of mRNA Abundance and Function of HLA‐linked Genesa
Authors: FU YINENG , YAN GANG , SHI LIJIA , FAUSTMAN DENISE
Published: February 2006

Abstract: Quantitative defects in the density of conformationally correct human lymphocyte antigen (HLA) class I complexes on the surface of lymphocytes are apparent in patients with diverse HLA‐linked autoimmune diseases, including Type I diabetes and Sjögren's syndrome. First, HLA class I expression was investigated in individuals with two rare and genetically divergent polyglandular autoimmune diseases. Polyglandular failure patients whose disease showed HLA linkage, but not those whose disease was not HLA linked, exhibited decreased HLA class I expression on the surface of their lymphocytes as well as a reduced abundance of transcripts of the HLA‐linked genes Tap1 and Tap2, both of which encode proteins that contribute to HLA class I processing. Second, lymphocytes from patients with insulin‐dependent diabetes mellitus (IDDM), Sjögren's syndrome, Graves' disease, and Hashimoto's disease showed varying degrees of decreased abundance of mRNAs that encode Tap1, Tap2, Lmp2, or Lmp7 (the latter two proteins also contribute to HLA class I processing). Third, in twins discordant for IDDM, reduced transcript abundance was preferential to diabetic subjects. Fourth, functional assays of isolated diabetic proteasomes, the peptide cutting complex containing LMP2 and LMP7 proteins, revealed altered peptidase activity. These data suggest that defective transcription of HLA class I‐processing genes could contribute to the quantitative defect in cell‐surface expression in autoimmune lymphocytes of HLA‐controlled disease.
Somatic Gene Transfer to Salivary Glands
Authors: O'CONNELL BRIAN C. , LILLIBRIDGE C. DAVID , AMBUDKAR INDU , KRUSE DAVID
Published: February 2006

Abstract: Recent developments in gene transfer technology have expanded the range of in vivo experimentation and provided new insights that might be applicable to the treatment of human diseases. Somatic gene transfer may complement conventional transgenic animal experiments by allowing for more restricted gene expression. Salivary glands of rats are readily transduced in vivo by adenovirus vectors. This model has been used to demonstrate the effects of transferring a water channel (aquaporin) gene to glands that have been damaged by radiation. Submandibular glands that receive the aquaporin vector increase the stimulated salivary flow close to normal levels. The possible role of E2F1 in promoting cell regeneration in vivo was also explored. A vector expressing E2F1 was capable of increasing DNA synthesis in rat salivary glands, though complete mitosis was not observed. Future generations of vectors must overcome current limitations of efficiency, immunogenicity, and transient expression.
Studying Development of Disease Through Temporally Controlled Gene Expression in the Salivary Glanda
Authors: FURTH PRISCILLA A. , LI MINGLIN , HENNIGHAUSEN LOTHAR
Published: February 2006

Abstract: Multistep tumorigenesis proceeds through activation of oncogenes and inactivation of tumor suppressor genes. Initiating oncoproteins induce secondary changes that maintain transformation in the absence of original stimuli. Time‐dependent reversal of SV40 T antigen (TAg)‐induced hyperplasia was studied using temporally controlled gene expression. Targeting TAg expression to the submandibular salivary gland of transgenic mice produces focal hyperplasias at age two weeks, which extend through large areas of the gland by four months. At twelve months, fibrosis and tumor foci accompany hyperplasia. Hyperplasia reverses when TAg expression is discontinued at four months but not at seven months. Secondary changes that maintain transformation appear to be time dependent. The system can be used to identify genetic events resulting in phenotypic reversal at four months and to expose factors preventing its occurrence at seven months. Expression of other proteins can be targeted to the salivary gland, and temporally controlled gene deletions can also be made using this system.
Sphingosine‐1‐Phosphate as an Intercellular Signaling Moleculea
Authors: IGARASHI YASUYUKI
Published: February 2006

ABSTRACT: Sphingosine‐1‐phosphate (Sph‐1‐P) has been implicated as an intracellular second messenger in many studies. Previously, we found the roles of Sph‐1‐P as a platelet activating lipid released from stimulated platelets and as a lipid regulator of cell motility. We first investigated the mechanism by which Sph‐1‐P induces activation in platelets. Although exogenous Sph‐1‐P activated platelets, intracellular Sph‐1‐P formed from exogenously added Sph failed to do so. Supporting the notion that exogenous Sph‐1‐P stimulates platelets from outside, we found that contact of platelet surfaces with Sph‐1‐P‐immobilized glass beads resulted in platelet activation. Using these glass beads, we next found that exogenously added Sph‐1‐P inhibits F10 cell motility from outside through its specific binding site(s) on the cell. We finally identified putative receptor protein(s) for Sph‐1‐P on the surface of F10 cells.
Metabolic Fate of Exogenous Sphingosine in Neuroblastoma Neuro2A Cells: Dose‐dependence and Biological Effectsa
Authors: RIBONI LAURA , BASSI ROSARIA , CAMINITI ANTONELLA , PRINETTI ALESSANDRO , VIANI PAOLA , TETTAMANTI GUIDO
Published: February 2006

ABSTRACT: The possible relationship between metabolism and biological effects of sphingosine was investigated in Neuro2a cells. [C3‐3H]‐sphingosine, administered at different doses (80 pmol‐80 nmol/mg cell protein). Amounts up to hundredfold were rapidly taken up and metabolized, the intracellular content of sphingosine being processed within 2 h. At low doses, [3H]‐sphingosine represented a minor portion of the cellular radiolabel, and N‐acylated metabolites, particularly ceramide, prevailed over degradation products. Neuro2a cell differentiation took place in conjunction with ceramide increase. At increasing exogenous sphingosine/cell ratio, the acylation process became saturated while sphingosine degradation increased proportionally. From this point on [3H]‐sphingosine accumulated and cell toxicity occurred. In conclusion, in Neuro2a cells the biological effects exerted by exogenous sphingosine are strictly connected to the exogenous sphingosine/cell ratio and to the capacity of the cell to metabolize sphingosine.
Sphingolipids as Receptor Modulators: An Overview
Authors: YATES ALLAN J. , RAMPERSAUD ARFAAN
Published: February 2006

ABSTRACT: Glycosphingolipids are amphipathic compounds that exist mainly in the plasmalemma with their oligosaccharide portion protruding into the extracellular environment. In this position they are admirably situated for interacting with both ligands and receptors. Binding studies have demonstrated that specific glycolipids function as receptors for some microorganisms and bacterial toxins. Specific oligosaccharides on both glycolipids and glycoproteins bind members of the selection families, and some gangliosides facilitate integrins binding to their ligands. Gangliosides modulate the trophic factor‐stimulated dimerization, tyrosine phosphorylation, and subsequent signal transduction events of several tyrosine kinase receptors. GM3 inhibits both the epidermal growth factor receptor and basic fibroblast factor receptor; several gangliosides except GM3 inhibit the platelet‐derived growth‐factor receptor; GM1 enhances nerve growth‐factor‐stimulated activation of TrkA; insulin receptor is inhibited to varying degrees by several gangliosides, but 2→3 sialosylparagloboside is most effective. Activities of the β1‐adrenergic and δ‐opioid receptors are modulated by GM1. Available information suggests that glycolipids serve as coordinators of multiple receptor functions.
Differential Involvement of Gangliosides versus Phospholipids in the Process of Temperature Adaptation in Vertebrates: A Comparative Phenomenological and Physicochemical Study
Authors: RAHMANN H. , JONAS U. , KAPPEL T. , HILDEBRANDT H.
Published: February 2006

ABSTRACT: The data presented support the idea that gangliosides are involved in thermal adaptation of neuronal membranes. Brain ganglioside patterns from cold‐blooded vertebrate species living in different climates and from mammals during ontogenetical or seasonal changes in their body temperature were compared. The general rule “the lower the environmental temperature the more polar is the composition of brain gangliosides” as derived from these data was confirmed by the changes in ganglioside patterns evoked by experimentally induced cold acclimation of fish. To assess whether gangliosides are able to modulate the temperature‐dependent properties of membranes, artificial mono‐ and bilayer membrane model systems were used. Incorporation of gangliosides in the model bilayer membranes evoked drastic changes in the dynamics of a peptide channel, suggesting that gangliosides are able to modulate basic membrane properties. In addition, data on thermosensitivity of ganglioside‐calcium interactions and on surface behavior of gangliosides in monolayers are reviewed.
GM1 Ganglioside‐induced Modulation of Opioid Receptor‐mediated Functions
Authors: CRAIN STANLEY M. , SHEN KE‐FEI
Published: February 2006

Electrophysiologic studies of dorsal‐root ganglion (DRG) neurons in culture have demonstrated both excitatory (Gs‐coupled) as well as inhibitory (Gi/Go‐coupled) opioid receptor‐mediated actions. Brief treatment of DRG neurons with cholera toxin‐B which binds specifically to GM1 sites on neuronal membranes, selectively blocks opioid excitatory but not inhibitory effects. Conversely, after brief treatment of DRG neurons with GM1, but not with GM2, GM3, or other related gangliosides, the threshold concentration of opioid agonists for eliciting excitatory effects is markedly decreased from nM to pM‐fM levels and opioid antagonists, for example, naloxone (NLX), at low nM concentrations paradoxically elicit excitatory effects. These studies suggest that the excitatory opioid supersensitivity of GM1‐treated DRG neurons is due primarily to increased efficacy of excitatory opioid‐receptor activation of Gs. Recent studies of cloned δ opioid receptors transfected into CHO cells suggest that this supersensitivity of GM1‐treated DRG neurons may be further augmented by rapid conversion of many opioid receptors from a Gi/Go‐coupled inhibitory mode to a Gs‐coupled excitatory mode. The opioid excitatory supersensitivity elicited in DRG neurons by acute elevation of exogenous GM1 provides novel insights into mechanisms underlying opioid tolerance and dependence, since remarkably similar supersensitivity occurs in DRG and other neurons after chronic treatment with morphine or other opioid agonists that upregulate endogenous GM1.
The Role of GM1 Ganglioside in Regulating Excitatory Opioid Effectsa
Authors: WU G. , LU Z.‐H. , WEI T. J. , HOWELLS R. D. , CHRISTOFFERS K. , LEDEEN R. W.
Published: February 2006

ABSTRACT: Our studies with cultured cells have provided new insight into the particular role of GM1 in regulating excitatory opioid responses. GM1 is significantly elevated in chronic opioid‐treated cells via Gs/adenylyl cyclase activation. Such GM1 elevation promotes coupling of opioid receptor with Gs, resulting in attenuation of inhibitory opioid effects and induction of a sustained excitatory response. Application of exogenous GM1, but not other gangliosides, induces excitatory opioid responses not only in neurons and neuroblastoma cells that bear intrinsic opioid receptors but also in nonneuronal cells that are transfected with δ‐opioid receptor. The latter system provides evidence that allosteric binding of GM1 changes receptor conformation from a Gi‐coupled to a Gs‐coupled mode. This is supported by preliminary experiments with a mutated δ‐opioid receptor.
Regulatory Roles for Sphingolipids in the Growth of Polarized Neuronsa
Authors: FUTERMAN ANTHONY H. , BOLDIN SWETLANA , BRANN ADI B. , SCHWARZ ANDREAS , ZISLING RIVKA
Published: February 2006

ABSTRACT: Over the past few years, our laboratory has focused on defining the regulatory roles of sphingolipids at various stages of neuronal development. These studies have been performed using primary cultures of hippocampal neurons, which are unique among neuronal cultures inasmuch as they develop by a well‐characterized and stereotypic sequence of events that gives rise to fully differentiated axons and dendrites. The data demonstrate that sphingolipids play at least three distinct roles in regulating neuronal development, namely (1) that ceramide enhances the formation of minor neuronal processes from lamellipodia, (2) that glucosylceramide synthesis is required for both normal and accelerated axon growth, and (3) that at both of these stages of development, ceramide induces apoptotic cell death at high concentrations. These observations are consistent with the possibility that minor process formation and apoptosis are regulated by ceramide‐dependent signaling pathways, whereas axonal growth may require GlcCer synthesis to support an intracellular transport pathway.
GM2 Ganglioside as a Regulator of Pyramidal Neuron Dendritogenesisa
Authors: WALKLEY STEVEN U. , SIEGEL DONALD A. , DOBRENIS KOSTANTIN , ZERVAS MARK
Published: February 2006

ABSTRACT:One of the most profound events in the life of a neuron in the mammalian CNS is the development of a characteristic dendritic tree, yet little is understood about events controlling this process. Pyramidal neurons of the cerebral cortex are known to undergo a single explosive burst of dendritic sprouting immediately after completing migration to the cortical mantle, and following maturation there is no evidence that new, primary dendrites are initiated. Yet in one group of rare genetic diseases‐Tay‐Sachs disease and related neuronal storage disorders‐cortical pyramidal neurons undergo a second period of dendritogenesis. New dendritic membrane is generated principally at the axon hillock and in time is covered with normal‐appearing spines and synapses. In our studies of normal brain development and storage diseases we consistently find one feature in common in cortical pyramidal neurons undergoing active dendritogenesis: They exhibit dramatically increased expression of GM2 ganglioside localized to cytoplasmic vacuoles within neuronal perikarya and proximal dendrites. There is also evidence that the increase in GM2 precedes dendritic spouting, and that after dendritic maturation is complete (in normal brain) the GM2 levels in neurons become substantially reduced. These findings are consistent with GM2 ganglioside playing a pivotal role in the regulation of dendritogenesis in cortical pyramidal neurons.
Significance of Gangliosides in Neuronal Differentiation of Neuroblastoma Cells and Neurite Growth in Tissue Culture
Authors: RÖSNER HARALD
Published: February 2006

ABSTRACT:Addition of dl‐threo‐1‐phenyl‐2‐decanolylamine‐3‐morpholino‐1‐propanol HCl (PDMP; 7–24 μM) or Fumonisin B1(FB1; 30–50 μM) to SH‐SY5Ytrk‐Ahuman neuroblastoma cells results within 4 days in a 40% decrease of the ganglioside content and in a reduction of nerve‐growth‐factor (NGF) ‐induced outgrowth of neuritic processes. NGF‐induced enhancement of GAP‐43 expression was not affected. However, unlike controls, immunostained GAP‐43 appeared concentrated in defined areas of cell perikarya and mostly absent from cell processes. Presence of 20‐μM exogenous GM1 for 4 days in NGF and PDMP containing cell cultures led to an increase of cell‐associated GM1 (15‐fold), GM2 (10‐fold), GM3 (15‐fold), GD1a (4‐fold), GD2, GD1b, and GT1b (all 3‐fold), and partially reversed the PDMP (and FB1) effects on neurite growth and GAP‐43 distribution. In a newly developed neuronal tissue culture system, PDMP and FB1led to a comparable dose‐dependent inhibition of neurite outgrowth from embryonic chicken spinal cord explants, which had been embedded into a fibrin matrix. In this system, addition of GM1 led to a further inhibition of neurite growth, probably due to an interaction with growth‐promoting components present in the surrounding fibrin matrix.
Glycosphingolipid Biosynthesis May Not Be Necessary for Vertebrate Brain Developmenta
Authors: BRIGANDE JOHN V. , SEYFRIED THOMAS N.
Published: February 2006

ABSTRACT: Glycosphingolipids (GSLs) in general and gangliosides in particular have long been considered essential for CNS growth and development. Recent studies with intact developing systems in fish and mice challenge this general notion. These studies suggest that glycosphingolipid biosynthesis and expression is neither essential nor necessary for neural growth and differentiation in the developing vertebrate brain. Rather than having a major role in neural cell growth and morphogenesis, the GSLs may have a role in modulating such membrane properties as signaling, electrical conduction, maintenance, and stability.
A Synthetic Ceramide Analog (l‐PDMP) Up‐regulates Neuronal Function
Authors: INOKUCHI JIN‐ICHI , MIZUTANI AKIHIRO , JIMBO MASAYUKI , USUKI SEIGOU , YAMAGISHI KIWAMU , MOCHIZUKI HIDEO , MURAMOTO KAZUYO , KOBAYASHI KAZUO , KURODA YOICHIRO , IWASAKI KATSUNORI , OHGAMI YUSUKE , FUJIWARA MICHIHIRO
Published: February 2006

ABSTRACT: To address the role of brain gangliosides in synaptic activity, the ceramide analogs, d‐threo‐1‐phenyl‐2‐decanoylamino‐3‐morpholino‐1‐propanol (d‐PDMP) and its enantiomer, l‐PDMP, were used to inhibit and stimulate ganglioside biosynthesis in cultured cortical neurons. Prolonged treatment with both PDMP isomers exhibited opposite effects on functional synapse formation measured by spontaneous synchronized oscillatory activity of intracellular Ca2+ between the neurons: suppression by d‐PDMP and facilitation by l‐PDMP. Up‐regulation of synaptic activity by l‐PDMP could be correlated with the slow but robust activation of p42 mitogen‐activated protein kinase. Treatment with l‐PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well‐learned spatial memory by an 8‐arm maze task, suggesting a new potential therapeutic approach for neurodegenerative disorders.
Gangliosides and Sialylcholesterol as Modulators of Synaptic Functionsa
Authors: ANDO SUSUMU , TANAKA YASUKAZU , WAKI HATSUE , KON KAZUO , IWAMOTO MACHIKO , FUKUI FUMIKO
Published: February 2006

ABSTRACT: Gangliosides were shown to enhance the release of acetylcholine from synaptosomes on stimulation. The influx of calcium ion into synaptosomes on membrane depolarization was increased by gangliosides. This was hypothesized to be an underlying mechanism for the enhancement of acetylcholine release. Studies using calcium channel blockers revealed that four distinct types of voltage‐dependent calcium channels occurred in cerebrocortical synapses, and that the N‐type was primarily responsible for the evoked release of acetylcholine. An additional result suggests that gangliosides may act mainly on the N‐type calcium channel. Cholinergic‐specific gangliosides, Chol‐1α, were assumed to participate in the mechanism of high‐affinity choline uptake. These two different actions of gangliosides were found to be mimicked by synthetic ganglioside analogs. Calcium influx was increased by α‐sialylcholesterol, and choline uptake was accelerated by β‐sialylcholesterol. Gangliosides and sialylcholesterol having these apparently beneficial effects were shown to ameliorate decreased functions of synapses from aged brains.
The Semisynthetic Glycosphingolipid LIGA20 Potently Protects Neurons Against Apoptosis
Authors: SAITO MARIKO , GUIDOTTI ALESSANDRO , BERG MARTIN J. , MARKS NEVILLE
Published: February 2006

ABSTRACT: LIGA20 (a semisynthetic GM1 with N‐dichloroacetyl sphingosine) having antinecrotic properties was evaluated as an antiapoptotic agent using cerebellar granule cells as a neuronal model. Neurons exposed to medium containing 5 μM K+ in absence of serum (apoptotic medium) for up to 22 h resulted in 65% cell death, accompanied by oligonucleosomal laddering, and a 15‐fold‐increase in caspase‐3 activity. The relationships between times required for enzyme activation and cell death suggests a linkage between these two events. Pretreatment with 10 μM LIGA20 for 10 min significantly attenuated the aforementioned apoptotic changes. LIGA20 also attenuated apoptosis induced by Pb2+, ethanol, and C6‐ceramide. Data show that LIGA20 is a versatile neuroprotective agent protecting cells from multiple pathways of cell death.
Promotion of Neuronal Survival by GM1 Ganglioside: Phenomenology and Mechanism of Action
Authors: FERRARI GIOVANNA , GREENE LLOYD A.
Published: February 2006

ABSTRACT: The purpose of this article is to review recent findings regarding the mechanisms by which GM1 may mimic or potentiate certain actions of neurotrophic factors, including promotion of neuronal survival. It is proposed that the neuroprotective activity of GM1 is due, at least in part, to its ability to favor the dimerization of neurotrophic factor receptor tyrosine kinases and thereby mimicking the action of their corresponding ligands. This may manifest both in the absence of ligand (thereby triggering a subset of neurotrophic‐factor responses such as prevention of apoptosis) and in the presence of ligand (thereby potentiating responses to neurotrophic factors).
The Role of Glycosphinglipids in Neurological Disorders: Mechanisms of Immune Actiona
Authors: YU ROBERT K. , ARIGA TOSHIO
Published: February 2006

ABSTRACT: Specific criteria that are required for understanding the significance of glycosphingolipid (GSL) antibodies, as well as mechanisms that may underlie the immunopathogenesis of these disorders, are proposed. These criteria are illustrated by describing the role of a unique family of acidic GSLs, the sulfated glucuronosyl glycolipids (SGGLs), in the pathogenic mechanisms of peripheral neuropathy with IgM paraproteinemia. High anti‐SGGL antibody titers are detected in patients suffering from this disorder. It is demonstrated that SGGLs, which possess a common carbohydrate epitope with myelin‐associated glycoprotein (MAG), several low‐molecular‐weight glycoproteins in the PNS, and a number of cell adhesion molecules, are potential target antigens for the neuropathy. Evidence is provided that sensitization of laboratory animals with pure SGGLs elicits experimental peripheral neuropathies that exhibit remarkable similarities with respect to antibody specificity, and electrophysiological and pathological features to the human conditions. By intraneural injection of antibodies into the sciatic nerve of rats, it is demonstrated that pathological changes consisting of demyelination and axonal degeneration are mediated by an antibody‐ and complement‐dependent process. To elucidate the mechanisms of antibody penetration from circulation into the endoneurial space, it is further shown that brain microvascular endothelial cells express SGGLs. Moreover it has been found that inflammatory cytokines are capable of upregulating the expression of SGGLs on the endothelial cell surface, resulting in a greater attachment of leukocytes. This latter observation suggests that SGGLs may also participate in cell‐mediated responses in certain inflammatory neurological disorders.
Molecular Mimicry in Guillain‐Barré Syndromea
Authors: SHEIKH K. A. , HO T. W. , NACHAMKIN I. , LI C. Y. , CORNBLATH D. R. , ASBURY A. K. , GRIFFIN J. W. , MCKHANN G. M.
Published: February 2006

ABSTRACT: Guillain‐Barré syndrome (GBS) is the commonest cause of acute flaccid paralysis worldwide. Recent pathological and electrodiagnostic studies indicate that there are different patterns within this syndrome. The demyelinating pattern predominates in North America and Europe, whereas axonal variants of GBS occur more frequently in Northern China. Infection with Campylobacter jejuni is one of the most frequently recognized antecedent events in all variants of GBS. The lipopolysaccharides of these organisms share ganglioside‐like epitopes with peripheral nerves, and patients with GBS have antiganglioside antibodies. These observations have given rise to the hypothesis that “molecular mimicry” is the immunopathogenic mechanism of injury to peripheral nerve fibers. With this hypothesis in view, we summarize our experience of GBS as it occurs in Northern China. To explore the role of molecular mimicry in this cohort we sought evidence of preceding Campylobacter infection and correlated this with clinical characteristics and antiganglioside serology. Based on our results we propose a sequence of pathogenic events leading to peripheral nerve injury in GBS.
Antiglycolipid Antibodies in Motor Neuropathiesa
Authors: BAUMANN NICOLE , HARPIN MARIE‐LUCE , MARIE YANNICK , LEMERLE KARINE , CHASSANDE BENEDICTE , BOUCHE PIERRE , MEININGER VINCENT , YU ROBERT K. , LÉGER JEAN‐MARC
Published: February 2006

ABSTRACT: In peripheral neuropathies with monoclonal gammopathy, mainly IgM, it appears clear from clinical, electrophysiological, and experimental data, that the target glycolipid or glycolipid epitope for the IgM is related to the type of neuropathy‐purely sensory, predominantly sensory, or uniquely motor. Investigations have focused on chronic peripheral neuropathies associated with polyclonal IgM reactivity to glycolipids. Although IgM anti‐GM1 antibodies are present in normal controls, there is a subgroup of motor neuropathies with high titer anti‐GM1 antibodies, mainly multifocal neuropathies with conduction blocks (MMNCB). Another subgroup of MMNCB may include IgM anti‐SGPG antibodies that do not cross‐react with MAG. The importance of the fine structure of the epitope has to be considered in view of the pathogenicity of the antibody. It may bear consequences on its binding properties on the neuronal surfaces and on its biological implications.
Guillain‐Barré Syndrome and Fisher's Syndrome Following Campylobacter jejuni Infectiona
Authors: YUKI NOBUHIRO , MIYATAKE TADASHI
Published: February 2006

ABSTRACT: The patients with Guillain‐Barré Syndrome (GBS) subsequent to Campylobacter jejuni enteritis showed axonal degeneration and had IgG anti‐GM1 antibody. The most frequently isolated C. jejuni from the patients was specific serotype of Penner's 19 in Japan. In the lipopolysaccharide (LPS) in C. jejuni of this serotype, the same oligosaccharide structure as GM1 ganglioside existed, suggesting the molecular mimicry between GM1 in nervous tissue and C. jejuni LPS. IgG anti‐GM1 antibody may bind the nodes of Ranvier and axon terminals and causes degeneration of the motor axon.

Some patients develop Fisher's syndrome following C. jejuni infection. C. jejuni strains from the patients who had IgG anti‐GQ1b antibody in the acute phase had GQ1b epitope in their LPS, and the molecular mimicry between GQ1b in nervous tissue and an antecedent infectious agent was clarified.
The Role of the Monosialoganglioside, GM1, as a Neuroprotectant in an Experimental Model of Cardiopulmonary Bypass and Hypothermic Circulatory Arresta
Authors: BAUMGARTNER WILLIAM A. , REDMOND J. MARK , ZEHR KENTON J. , BROCK MALCOLM V. , TSENG ELAINE E. , BLUE MARY E. , TRONCOSO JUAN C. , JOHNSTON MICHAEL V.
Published: February 2006

ABSTRACT: Twelve male dogs were placed on closed‐chest cardiopulmonary bypass, subjected to 2 h of HCA at 18°C, and rewarmed to 37°C on closed‐chest cardiopulmonary bypass. All animals were mechanically ventilated and monitored for 20 h before extubation and survived for 3 days. Group 1 dogs (n= 6) were pretreated with GM1, 30 mg/kg/ 24 h for 3 days before HCA, and received continuous infusion of GM1 during the procedure and 30 mg/kg/24 h for 3 days after HCA. Group 2 dogs (n= 6) received vehicle only. With a species‐specific behavior scale that yielded a neurodeficit score ranging from 0% (normal) to 100% (brain dead), all animals were neurologically assessed every 12 h by two observers. After death at 72 h, brains were examined by glutamate receptor autoradiography and by histologic examination for patterns of selective neuronal necrosis and were scored blindly from 0 (normal) to 100 (severe injury). These results provide evidence of a role for GE in the development of HCA‐induced brain injury and suggest that monosialogangliosides may have a neuroprotective effect in prolonged periods of HCA.
GM1 Ganglioside for Acute Ischemic Stroke: Trial Design Issues
Authors: ALTER MILTON
Published: February 2006

ABSTRACT: GM1 ganglioside decreases the severity of ischemic brain lesions in experimental models, although the mechanism is uncertain. In clinical trials involving patients with stroke, efficacy has been reported in some but not in others. However, some of the latter also showed efficacy after analyses not planned before the trial began. Analyses of the trials done to date revealed design differences sufficiently large so as to preclude meta‐analysis of the results. Moreover, flaws in these studies may account for some of their failure to demonstrate that GM1 therapy is efficacious in ischemic stroke. Several of these flaws are discussed, including small sample size; attrition of the study cohort; inclusion of stroke severity and type that made demonstrations of a beneficial effect difficult; use of inappropriate clinical and outcome measuring instruments; delay in enrollment; inappropriate statistical analyses; inadequate dose; inappropriate route of administration; a too short duration of treatment. Improvements in these design features in future clinical trials of GM1 may yet demonstrate efficacy of this drug in acute ischemic stroke.
Maternal and Transplacental Effects of Cocaine
Authors: WOODS JAMES R.
Published: February 2006

ABSTRACT: Pregnancy is a dynamic process, and maternal as well as fetal risks from cocaine use in pregnancy may differ as pregnancy progresses. Three areas of biology offer opportunities for reevaluating cocaine's effects in pregnancy: (1) Maternal cardiovascular and neurologic responses to cocaine hydrochloride are enhanced when compared with responses in nonpregnant subjects to the same dose per kilogram or to metabolites of crack cocaine. (2) During first trimester placental implantation, oxygen availability to the fetus may normally be limited. Cocaine‐induced uterine artery vasoconstriction may lead to reperfusion and oxygen toxicity to the fetus from released reactive oxygen species. (3) Cocaine transport in the first and early second trimester may, in part, be across the placental chorion‐amnion. Lacking a skin barrier, the fetus at mid‐pregnancy may come in direct contact with high concentrations of cocaine in amniotic fluid, a reservoir that clears cocaine slowly, thereby prolonging exposure during critical periods of fetal neurotransmitter formation. Exploring these three areas of biology may offer new approaches to understanding the ultimate impact of prenatal cocaine exposure on maternal and fetal biology.
Neonatal Neurobehavioral and Neuroanatomic Correlates of Prenatal Cocaine Exposure: Problems of Dose and Confounding
Authors: FRANK DEBORAH A. , AUGUSTYN MARILYN , ZUCKERMAN BARRY S.
Published: February 2006

ABSTRACT:Complex methodologic challenges face researchers studying the effects of prenatal cocaine exposure on infant outcome. These include unavoidable imprecision in ascertaining the gestational timing and dose of cocaine to which the fetus was exposed and difficulties in identifying and quantifying the confounding, mediating, and moderating variables. Review of research on neonatal behavioral and cranial ultrasound findings followingin uterococaine exposure is used to illustrate these issues. We conclude that there are measurable but not dramatic dose‐related effects of prenatal cocaine exposure on infant central nervous system structure and function. The effects of dose of prenatal cocaine exposure on later child development remain to be determined. Such research would be facilitated by a scientific consensus delineating relative doses of prenatal cocaine exposure.
Selective Direct Toxicity of Cocaine on Fetal Mouse Neurons: Teratogenic Implications of Neurite and Apoptotic Neuronal Loss
Authors: NASSOGNE MARIE‐CÉCILE , EVRARD PHILIPPE , COURTOY PIERRE J.
Published: February 2006

ABSTRACT:This chapter reviews epidemiologic clinical surveys and experimental animal studies, indicating that cocaine may induce severe teratogenic effects on the developing brain. Evidence for direct toxic effects is next presented. Using cocultures of embryonic brain cells, we demonstrate that cocaine selectively affects neuronal cells, first causing a dramatic reduction in the number and length of neurites, then extensive neuronal death by apoptosis. By contrast, cocaine affected neither the abundance of astroglial cells nor their glial fibrillary acidic protein content. These effects are not due to cocaine metabolites. The contributions of indirect and direct effects that could account for cocaine neuroteratogenicity are finally discussed.
Animal Behavior Models: Increased Sensitivity to Stressors and Other Environmental Experiences after Prenatal Cocaine Exposurea
Authors: SPEAR LINDA P. , CAMPBELL JAMES , SNYDER KRISTYN , SILVERI MARISA , KATOVIC NINA
Published: February 2006

ABSTRACT: Neural compensations occurring after prenatal cocaine exposure may often permit some functional recovery, although the cost of this reorganization may be a decrease in adaptability. As we have seen in our rodent model of prenatal cocaine exposure, latent deficits may become unmasked when offspring are exposed to cognitive and environmental demands and stressors. In adolescence and adulthood, offspring exposed gestationally to cocaine exhibit characteristic decreases in stress‐induced immobility along with increases in aggression under the demands of social competition. Recently, we observed that cocaine‐exposed offspring are also unusually sensitive to the long‐term effects of early manipulation (noninvasive heart rate testing at 16 days of age). When tested in adulthood, cocaine‐exposed offspring not receiving this early experience exhibited less immobility when tested in the presence of intermittent footshock or when subsequently examined in an open field as well as more locomotion in the open field than control offspring, findings reminiscent of previous work. By contrast, these effects were normalized (shock‐induced immobility) or reversed (open field immobility and locomotion) in cocaine‐exposed animals given the early experience. This marked susceptibility to the effects of early manipulation was less evident in control offspring and even in a group of stunted nutritional controls. Thus, cocaine‐exposed offspring may exhibit increased sensitivity not only to environmental demands and stressors, but also to the potential moderating or beneficial effects of early experiences.
Neurological Correlates of Fetal Cocaine Exposurea
Authors: CHIRIBOGA CLAUDIA A.
Published: February 2006

ABSTRACT: Cocaine is a highly psychoactive substance with numerous effects that readily crosses the placenta, achieving variables levels in the fetus. Determining whether prenatal exposure to cocaine and its metabolites damages the developing human nervous system is hindered by the multiple intervening factors (confounders) that plague clinical settings, which warrant consideration in controlled studies. Prenatal cocaine exposure has been linked to numerous adverse neonatal outcomes, affecting fetal growth (i.e., low birth weight, intrauterine growth retardation, and small head size) and neurobehavior. These neurobehavior effects span the gamut from no abnormalities to impairments in arousal, neurological function, neurophysiological function, and state regulation. Strokes and possibly seizures are also noted. Dose‐response effects of fetal cocaine exposure on fetal growth and neonatal neurobehavior are reported using quantitative methods of ascertainment. In early infancy, irritability and hypertonia are also described. Most cocaine associations are transient and resolve in infancy and early childhood. Whether such transient abnormalities place infants at increased risk for later neurodevelopmental impairments is not known. Controlled studies have found no cognitive differences related to prenatal cocaine exposure among toddlers or school age children, except as mediated through effects on head growth. Anecdotally, cocaine‐exposed children seem to suffer from neurobehavioral abnormalities, but to date controlled studies have not established an association between cocaine and behavioral disorders, except for inattentiveness. Despite encouraging reports, the question of whether cocaine exerts long‐term adverse effects on the developing human nervous system has not yet been resolved, largely because of the limitations of existing studies that rely on inadequate, mostly qualitative ascertainment of cocaine exposure as well as the dearth of studies in older children. Such methodological limitations may have compromised our ability to identify cocaine‐exposed children at most risk.
Regulation of Arousal and Attention in Preschool Children Exposed to Cocaine Prenatally
Authors: MAYES LINDA C. , GRILLON CHRISTIAN , GRANGER RICHARD , SCHOTTENFELD RICHARD
Published: February 2006

ABSTRACT:Four lines of evidence suggest a plausible link between prenatal cocaine exposure (CE) and specific effects on the mechanisms subserving arousal and attention regulation in infants and preschool‐aged children. These are (1) the association of prenatal CE with alterations in monoaminergic system ontogeny; (2) neurobehavioral effects of prenatal CE in animals consistent with an enduring increased level of activity in response to novelty and inhibited exploration and altered responses to stress, suggesting overarousal in the face of novel/stressful situations and disrupted attention and exploration; (3) altered norepinephrine system function in cocaine‐exposed human infants; and (4) neurobehavioral findings in infants and preschool‐aged children suggestive of disrupted arousal regulation in the face of novelty, increased distractibility, and consequent impaired attention to novel, structured tasks. This paper summarizes findings on response to novel challenges from a cohort of prenatally cocaine‐exposed infants and preschool‐aged children followed longitudinally since birth. Arousal regulation in the face of novel challenges is operationalized behaviorally as state and emotional reactivity and neurophysiologically as the startle response and heart rate variability. Across different ages and tasks, behavioral and neurophysiological findings suggest that prenatally cocaine‐exposed children are more likely to exhibit disrupted arousal regulation. Because the regulation of arousal serves as a gating mechanism to optimize orientation and attention, arousal regulation has important implications for ongoing information processing, learning, and memory. Furthermore, impaired arousal regulation predisposes children to a lower threshold for activation of “stress circuits” and may increase their vulnerability to the developmentally detrimental effects of stressful conditions particularly when such children are also exposed to the chaotic environmental conditions often characterizing substance‐abusing families.
Prenatal Cocaine Exposure: A Longitudinal Study of Developmenta
Authors: RICHARDSON GALE A.
Published: February 2006

ABSTRACT: The current study examines the effect of prenatal cocaine use on physical, cognitive, and behavioral development at birth, 1, 3, and 7 years, controlling for other factors that affect child development. Women who used cocaine during pregnancy were more likely to be single and to use alcohol, marijuana, and tobacco than were women who did not use cocaine. Prenatal cocaine use was associated with reduced gestational age, but not with birth weight, length, or head circumference. Neonatal neurobehavioral assessments were affected by prenatal cocaine exposure. Growth at 1 year was not affected by prenatal cocaine use. At 3 years, prenatal cocaine use was a significant predictor of head circumference and of the composite score on the Stanford‐Binet Intelligence Scale (4th edition). Prenatal cocaine use was also associated with temperamental differences at 1 and 3 years and with behavior problems at 3 years. These findings represent a pattern of central nervous system effects, related to prenatal cocaine exposure, which is predicted by the teratologic model.
Changes in the Midbrain‐Rostral Forebrain Dopamine Circuitry in the Cocaine‐Exposed Primate Fetal Braina
Authors: RØNNEKLEIV OLINE K. , FANG YUAN , CHOI WAN S. , CHAI LIN
Published: February 2006

ABSTRACT: To ascertain cocaine's effects in the fetus, we developed a nonhuman primate model in which pregnant monkeys were administered cocaine (3 mg/kg im) or saline four times a day from day 20 through days 40–70 of a 165‐day gestation. At the time of cesarean section, plasma levels of cocaine in fetal blood were 231 ± 70 ng/ml. Fetal brains were examined using immunocytochemistry, in situ hybridization, receptor autoradiography, and nuclease protection assay analysis. No differences were found in the expression of tyrosine hydroxylase and dopamine receptor mRNAs by days 40–45 of gestation. However, by day 60 the midbrain of monkeys exposed to cocaine had significantly reduced expression of tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Moreover, dopamine D1 and D2 receptor mRNAs were significantly elevated in the rostral forebrain as were D1 and D2 receptor binding sites in days 60–70 cocaine‐exposed fetuses. Cocaine treatment from day 20 to days 60 and 70 of gestation also significantly increased the mRNA concentrations of dynorphin and enkephalin in the rostral forebrain. These findings suggest that in utero cocaine exposure has profound effects on the developing dopamine neurocircuitry.