Showing papers in "Neurochemical Research in 2002"
TL;DR: The available data indicate that the anticonvulsant efficacy of these AEDs is mainly due to the inhibition of sodium channel activity, which is in line with previous reports on these drugs.
Abstract: Carbamazepine (CBZ) has been extensively used in the treatment of epilepsy, as well as in the treatment of neuropathic pain and affective disorders. However, the mechanisms of action of this drug are not completely elucidated and are still a matter of debate. Since CBZ is not very effective in some epileptic patients and may cause several adverse effects, several antiepileptic drugs have been developed by structural variation of CBZ, such as oxcarbazepine (OXC), which is used in the treatment of epilepsy since 1990. (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-024), which were recently developed by BIAL, are new putative antiepileptic drugs, with some improved properties. In this review, we will focus on the mechanisms of action of CBZ and its derivatives, OXC, BIA 2-093 and BIA 2-024. The available data indicate that the anticonvulsant efficacy of these AEDs is mainly due to the inhibition of sodium channel activity.
274 citations
TL;DR: This review describes mRNA biosynthesis and degradation, and detail the cis-elements and RNA-binding proteins known to affect mRNA turnover, and presents recent examples in which dysregulation of mRNA stability has been associated with human diseases including cancer, inflammatory disease, and Alzheimer's disease.
Abstract: Regulation of gene expression is essential for the homeostasis of an organism, playing a pivotal role in cellular proliferation, differentiation, and response to specific stimuli. Multiple studies over the last two decades have demonstrated that the modulation of mRNA stability plays an important role in regulating gene expression. The stability of a given mRNA transcript is determined by the presence of sequences within an mRNA known as cis-elements, which can be bound by trans-acting RNA-binding proteins to inhibit or enhance mRNA decay. These cis-trans interactions are subject to a control by a wide variety of factors including hypoxia, hormones, and cytokines. In this review, we describe mRNA biosynthesis and degradation, and detail the cis-elements and RNA-binding proteins known to affect mRNA turnover. We present recent examples in which dysregulation of mRNA stability has been associated with human diseases including cancer, inflammatory disease, and Alzheimer's disease.
220 citations
TL;DR: (AA-Se)2 and (AA-S)2 can be considered as potential pharmaceutical antioxidant agents, respectively, after thiobarbituric reactive species (TBARS) production by rat brain homogenates was determined colorimetrically.
Abstract: Ebselen (2-phenyl- 1,2-benzisoselenazole-3 (2H)-one) is a seleno-organic compound with antioxidant properties, and anti-inflammatory actions. Recently, ebselen improved the outcome of acute ischemic stroke in humans. In the present study, the potential antioxidant capacity of organochalcogenide compounds diphenyl diselenide (PhSe)2, diphenyl ditelluride (PhTe)2, diphenyl disulfide (PhS)2, p-Cl-diphenyl diselenide (pCl-PhSe)2, bis-[S-4-isopropyl 2-phenyl oxazoline] diselenide (AA-Se)2, bis-[S-4-isopropyl 2-phenyl oxazoline] ditelluride (AA-Te)2 and bis-[S-4-isopropyl 2-phenyl oxazoline] disulfide (AA-S)2 was compared with that of ebselen (a classical antioxidant). Spontaneous and quinolinic acid (QA)- (2 mM) and sodium nitroprusside (SNP)- (5 μM)-induced thiobarbituric reactive species (TBARS) production by rat brain homogenates was determined colorimetrically. TBARS formation was reduced by ebselen, (PhSe)2, (PhTe)2, (AA-Se)2, (AA-S)2 and (pCl- PhSe)2 to basal rates. The concentrations of these compounds needed to inhibit TBARS formation by 50% (lC50) are 1.71 μM, 3.73 μM, 1.63 μM, 9.85 μM, > 33.3 μM, 23.2 μM and 4.83 μM, respectively for QA. For TBARS production induced by SNP the lC50 was 2.02 μM, 12.5 μM, 2.80 μM, > 33.3 μM, 24.5 μM and 7.55 μM, respectively. The compounds (AA-Te)2 and (PhS)2 have no antioxidant activity and pro-oxidant activity, respectively. These results suggest that (AA-Se)2 and (AA-S)2 can be considered as potential pharmaceutical antioxidant agents.
192 citations
TL;DR: Data demonstrating consistently fewer oligodendrocytes in schizophrenics compared to controls point to a major involvement of oligodendedrocyte abnormalities in schizophrenia, and therapies modulating oligodends survival and differentiation may therefore be beneficial in schizophrenia.
Abstract: Our previous analyses in postmortem prefrontal cortex samples from a well-characterized cohort of severely affected schizophrenics and in matched controls demonstrated decreased expression of myelin and oligodendrocyte-related genes in the disease state. This decreased expression, now replicated in independent studies, suggests that there is a disruption of oligodendrocyte function and/or a loss of oligodendrocytes in schizophrenia. In the current report, we review expression studies in schizophrenia and present data demonstrating consistently fewer oligodendrocytes in schizophrenics compared to controls. The decrease in density reached 22% (p < 0.01) in layer III of area 9 and 20% (p < 0.02) in the white matter of the superior frontal gyrus. These data, when taken together with expression studies carried out by us and by other groups, and by imaging and other microscopic studies, point to a major involvement of oligodendrocyte abnormalities in schizophrenia. Therapies modulating oligodendrocyte survival and differentiation may therefore be beneficial in schizophrenia.
182 citations
TL;DR: Results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings, and changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered.
Abstract: Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D2-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA1 region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA1, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.
174 citations
TL;DR: The authors present a review of accepted taurine action and highlight recent discoveries regarding taurines and calcium homeostasis in neurons, including Na+-Ca2+ exchangers and metabotropic receptors mediating phospholipase-C.
Abstract: The effects of taurine in the mammalian nervous system are numerous and varied There has been great difficulty in determining the specific targets of taurine action The authors present a review of accepted taurine action and highlight recent discoveries regarding taurine and calcium homeostasis in neurons In general there is a consensus that taurine is a powerful agent in regulating and reducing the intracellular calcium levels in neurons After prolonged L-glutamate stimulation, neurons lose the ability to effectively regulate intracellular calcium This condition can lead to acute swelling and lysis of the cell, or culminate in apoptosis Under these conditions, significant amounts of taurine (mM range) are released from the excited neuron This extracellular taurine acts to slow the influx of calcium into the cytosol through both transmembrane ion transporters and intracellular storage pools Two specific targets of taurine action are discussed: Na+-Ca2+ exchangers, and metabotropic receptors mediating phospholipase-C
173 citations
TL;DR: The availability of the cDNA species encoding mammalian sialidases is an important step leading toward a comprehensive picture of the relationships between the structure and biological function of these enzymes.
Abstract: This review summarizes the recent research development on mammalian sialidase molecular cloning. Sialic acid-containing compounds are involved in several physiological processes, and sialidases, as glycohydrolytic enzymes that remove sialic acid residues, play a pivotal role as well. Sialidases hydrolyze the nonreducing, terminal sialic acid linkage in various natural substrates, such as glycoproteins, glycolipids, gangliosides, and polysaccharides. Mammalian sialidases are present in several tissues/organs and cells with a typical subcellular distribution: they are the lysosomal, the cytosolic, and the plasma membrane-associated sialidases. Starting in 1993, 12 different mammalian sialidases have been cloned and sequenced. A comparison of their amino acid sequences revealed the presence of highly conserved regions. These conserved regions are shared with viral and microbial sialidases that have been characterized at three-dimensional structural level, allowing us to perform the molecular modeling of the mammalian proteins and suggesting a monophyletic origin of the sialidase enzymes. Overall, the availability of the cDNA species encoding mammalian sialidases is an important step leading toward a comprehensive picture of the relationships between the structure and biological function of these enzymes.
165 citations
TL;DR: It was found that trkB and trkC mRNAs were selectively down-regulated in NB neurons, whereas p75NTR mRNA levels remained stable in end stage AD, and a selective up-regulation of cathepsin D mRNA in NB neuron in AD brain was found.
Abstract: Cholinergic neurons of the nucleus basalis (NB) are selectively vulnerable in Alzheimer's disease (AD), yet the molecular mechanisms associated with their dysfunction remain unknown. We used single cell RNA amplification and custom array technology to examine the expression of functional classes of mRNAs found in anterior NB neurons from normal aged and AD subjects. mRNAs encoding neurotrophin receptors, synaptic proteins, protein phosphatases, and amyloid-related proteins were evaluated. We found that trkB and trkC mRNAs were selectively down-regulated in NB neurons, whereas p75NTR mRNA levels remained stable in end stage AD. TrkA mRNA was reduced by approximately 28%, but did not reach statistical significance. There was a down-regulation of synaptophysin, synaptotagmin, and protein phosphatases PP1α and PP1β mRNAs in AD. In contrast, we found a selective up-regulation of cathepsin D mRNA in NB neurons in AD brain. Thus, anterior NB neurons undergo selective alterations in gene expression in AD. These results may provide clues to the molecular pathogenesis of NB neuronal degeneration during AD.
144 citations
TL;DR: In this chapter the methods for analysis of RNAs that are localized to dendrites are reviewed and a partial list of dendritically localized RNAs is presented, which may be useful in identifying RNA regulatory regions that are responsible for specifying rate of RNA transport and the dendritic sites at which targeted RNAs dock so that they can be translated.
Abstract: Targeting of mRNAs to distinct subcellular regions occurs in all polarized cells. The mechanisms by which RNA transport occurs are poorly understood. With the advent of RNA amplification methodologies and expression profiling it is now possible to catalogue the RNAs that are targeted to particular subcellular regions. In particular, neurons are polarized cells in which dendrites receive signals from presynaptic neurons. Upon stimulation (information receipt) the dendrite processes the information such that an immediate dendritic response is generated as well as a longer-term somatic response. The integrated cellular response results in a signal that can be propagated through the axon to the next post-synaptic neuron. Much previous work has shown that mRNAs can be localized in dendrites and that local translation in dendrites can occur. In this chapter the methods for analysis of RNAs that are localized to dendrites are reviewed and a partial list of dendritically localized RNAs is presented. This information may be useful in identifying RNA regulatory regions that are responsible for specifying rate of RNA transport and the dendritic sites at which targeted RNAs dock so that they can be translated.
127 citations
TL;DR: This work explored the subcellular expression pattern of monocarboxylate transporters (MCTs) by use of selective antibodies and high resolution immunogold cytochemistry and found that MCT1 was localized in the apical membrane of pigment epithelial cells and in the photoreceptor inner segment membrane in the retina.
Abstract: An efficient exchange of lactate between different cell types (such as astrocytes and neurones) would require that lactate transporters are expressed in contiguous parts of the respective plasma membranes. To settle this issue we explored the subcellular expression pattern of monocarboxylate transporters (MCTs) by use of selective antibodies and high resolution immunogold cytochemistry. We investigated whether the membrane domains containing MCT1, MCT2 and MCT4 are spatially related to each other and to other membrane domains, i.e. those containing glutamate receptors. We used retina and cerebellum as a model for our investigations. We found that MCT1 was localized in the apical membrane of pigment epithelial cells and in the photoreceptor inner segment membrane in the retina. In the brain MCT1 was present in endothelial cells. MCT2 was localized in the postsynaptic membrane of parallel fiber-Purkinje cell synapses and MCT4 was situated in the membrane of glial cells in the cerebellum.
120 citations
TL;DR: During a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated.
Abstract: The effects were studied of short-term (1 week) versus long-term (2-3 weeks) fluoxetine treatment of primary cultures of mouse astrocytes, differentiated by treatment with dibutyryl cyclic AMP. From previous experiments it is known that acute treatment with fluoxetine stimulates glycogenolysis and increases free cytosolic Ca2+ concentration ([Ca2+]i]) in these cultures, whereas short-term (one week) treatment with 10 μM down-regulates the effects on glycogen and [Ca2+]i, when fluoxetine administration is renewed (or when serotonin is administered). Moreover, antagonist studies have shown that these responses are evoked by activation of a 5-HT2 receptor that is different from the 5-HT2A receptor and therefore at that time tentatively were interpreted as being exerted on 5-HT2C receptors. In the present study the cultures were found by RT-PCR to express mRNA for 5-HT2A and 5-HT2B receptors, but not for the 5-HT2C receptor, identifying the 5-HT2 receptor activated by fluoxetine as the 5-HT2B receptor, the most recently cloned 5-HT2 receptor and a 5-HT receptor known to be more abundant in human, than in rodent, brain. Both short-term and long-term treatment with fluoxetine increased the specific binding of [3H]mesulergine, a ligand for all three 5-HT2 receptors. Long-term treatment with fluoxetine caused an agonist-induced up-regulation of the glycogenolytic response to renewed administration of fluoxetine, whereas short-term treatment abolished the fluoxetine-induced hydrolysis of glycogen. Thus, during a treatment period similar to that required for fluoxetine's clinical response to occur, 5-HT2B-mediated effects are initially down-regulated and subsequently up-regulated.
TL;DR: DNA microarray transcriptome profiling of the postmortem brain opens novel horizons in understanding molecular changes associated with complex psychiatric disorders and its goal will be to integrate this expression data within the context of the relevant anatomical, biochemical, molecular, imaging and clinical findings.
Abstract: DNA microarray transcriptome profiling of the postmortem brain opens novel horizons in understanding molecular changes associated with complex psychiatric disorders. With careful analysis and interpretation of microarray data we are uncovering previously unknown, expression patterns that maybe subject-specific and pivotal in understanding the disease process. In our recent studies, analyses of the prefrontal cortex of subjects with schizophrenia and matched controls uncovered complex changes in the expression of genes related to presynaptic secretory release, GABAergic and glutamatergic transmission, metabolic pathways, myelination, as well as cAMP and phosphoinositol second messenger systems. Our goal will be to integrate this expression data within the context of the relevant anatomical, biochemical, molecular, imaging and clinical findings.
TL;DR: The results indicate that oxidative stress is probably involved in the pathogenesis of homocystinuria and that reduction of Na+,K+-ATPase activity may be related to the neuronal dysfunction found in homocyStinuric patients.
Abstract: In the present study we evaluated the effect of acute homocysteine (Hcy) administration on Na(+),K(+)-ATPase activity, as well as on some parameters of oxidative stress such as total radical-trapping antioxidant potential (TRAP) and on activities of antioxidant enzymes catalase (CAT), superoxide dismutase and glutathione peroxidase in rat hippocampus. Results showed that Hcy significantly decreased TRAP, Na(+),K(+)-ATPase and CAT activities, without affecting the activities of superoxide dismutase and glutathione peroxidase. We also verified the effect of chronic pretreatment with vitamins E and C on the reduction of TRAP, Na(+),K(+)-ATPase and CAT activities caused by Hcy. Vitamins E and C per se did not alter these parameters, but prevented the reduction of TRAP, Na(+),K(+)-ATPase and CAT activities caused by Hcy. Our results indicate that oxidative stress is probably involved in the pathogenesis of homocystinuria and that reduction of Na(+),K(+)-ATPase activity may be related to the neuronal dysfunction found in homocystinuric patients.
TL;DR: Changes in brain lipid composition and metabolism due to aging involve an increase in acidic phospholipid synthesis and changes in the lipid second messengers diacylglycerol and phosphatidic acid are outlined.
Abstract: In this review, changes in brain lipid composition and metabolism due to aging are outlined. The most striking changes in cerebral cortex and cerebellum lipid composition involve an increase in acidic phospholipid synthesis. The most important changes with respect to fatty acyl composition involve a decreased content in polyunsaturated fatty acids (20:4n-6, 22:4n-6, 22:6n-3) and an increased content in monounsaturated fatty acids (18:1n-9 and 20:1n-9), mainly in ethanolamine and serineglycerophospholipids. Changes in the activity of the enzymes modifying the phospholipid headgroup occur during aging. Serine incorporation into phosphatidylserine through base-exchange reactions and phosphatidylcholine synthesis through phosphatidylethanolamine methylation increases in the aged brain. Phosphatidate phosphohydrolase and phospholipase D activities are also altered in the aged brain thus producing changes in the lipid second messengers diacylglycerol and phosphatidic acid.
TL;DR: Quantitative proteome analysis of Alzheimer's disease brains was performed using 2-D gels to identify disease specific changes in protein expression, which has tremendous potential as a means of determining the pathogenesis, detecting disease markers and potential targets for drug therapy in AD.
Abstract: Quantitative proteome analysis of Alzheimer's disease (AD) brains was performed using 2-D gels to identify disease specific changes in protein expression. The task of characterizing the proteome and its components is now practically achievable because of the development and integration of four important tools: protein, EST, and complete genome sequence databases, mass spectrometry, matching software for protein sequences and protein separation technology. Mass spectrometry (MS) instrumentation has undergone a tremendous change over the past decade, culminating in the development of highly sensitive, robust instruments that can reliably analyze biomolecules, particularly proteins and peptides; we identified 35 proteins from over 100 protein spots on a 2-D gel. Using this current technology, protein-expression profiling, which is actually a specialized form of mining, is an important principal application of proteomics. The information obtained has tremendous potential as a means of determining the pathogenesis, and detecting disease markers and potential targets for drug therapy in AD.
TL;DR: This review attempts to summarize findings in ganglioside function in eukaryotic cells and point to possible future directions of research.
Abstract: Ganglioside function in eukaryotic cells encompasses a variety of modulatory interactions related to both development and mature cellular behavior. In relation to the nervous system this includes induction of neurite outgrowth and trophic/neuroprotective phenomena; more generally this applies to ganglioside effects on receptor function, adhesion reactions, and signal transduction mechanisms in neural and extraneural systems. Underlying many of these trophic effects are ganglioside-induced changes in cellular calcium, accomplished through modulation of Ca2+ influx channels, Ca2+ exchange proteins, and various Ca2+-dependent enzymes that are altered through association with gangliosides. A clear distinction needs to be drawn between intrinsic functions of gangliosides as naturally expressed by the cell and activities created by application of exogenous ganglioside(s) that may or may not reflect natural function. This review attempts to summarize findings in this area and point to possible future directions of research.
TL;DR: The results suggest that the brain dysfunction found in homocystinuria may be related to the reduction of brain Na+,K+-ATPase activity.
Abstract: Hyperhomocysteinemia occurs in homocystinuria, an inherited metabolic disease clinically characterized by thromboembolic episodes and a variable degree of neurological dysfunction whose pathophysiology is poorly known In this study, we induced elevated levels of homocysteine (Hcy) in blood (500 μM), comparable to those of human homocystinuria, and in brain (60 nmol/g wet tissue) of young rats by injecting subcutaneously homocysteine (03-06 μmol/g of body weight) twice a day at 8-hr intervals from the 6th to the 28th postpartum day Controls received saline in the same volumes Na+,K+-ATPase and Mg2+-ATPase activities were determined in the hippocampus of treated Hcy- and saline-treated rats Chronic administration of Hcy significantly decreased (40%) Na+,K+-ATPase activity but did not alter Mg2+-ATPase activity Considering that Na+,K+-ATPase plays a crucial role in the central nervous system, our results suggest that the brain dysfunction found in homocystinuria may be related to the reduction of brain Na+,K+-ATPase activity
TL;DR: Neuroscientists have recently begun to explore the role of lysophospholipid receptors in a number of cell types; this research has implicated these receptors in the survival, migration, and differentiation of cells in the mammalian nervous system.
Abstract: The lysophospholipid mediators, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), are responsible for cell signaling in diverse pathways including survival, proliferation, motility, and differentiation. Most of this signaling occurs through an eight-member family of G-protein coupled receptors once known as the endothelial differentiation gene (EDG) family. More recently, the EDG receptors have been divided into two subfamilies: the lysophosphatidic acid subfamily, which includes LPA1, (EDG-2/VZG-1), LPA2 (EDG-4), and LPA3 (EDG-7), and the sphingosine-1-phosphate receptor subfamily, which includes S1P1 (EDG-1), S1P2 (EDG-5/H218/AGR16), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8/NRG-1). The ubiquitous expression of these receptors across species, coupled with their diverse cellular functions, has made lysophospholipid receptors an important focus of signal transduction research. Neuroscientists have recently begun to explore the role of lysophospholipid receptors in a number of cell types; this research has implicated these receptors in the survival, migration, and differentiation of cells in the mammalian nervous system.
TL;DR: Pyruvate recycling was demonstrated in astrocytes, indicating the ability of these cells to undertake complete oxidative degradation of glutamate, and mitochondrial malic enzyme is not operational, indicating that pyruvates are not up-regulated in the neuronal-astrocytic co-cultures.
Abstract: Pyruvate recycling was studied in primary cultures of mouse cerebrocortical astrocytes, GABAergic cerebrocortical interneurons, and co-cultures consisting of both cell types by measuring production of [4-(13)C]glutamate from [3-(13)C]glutamate by aid of nuclear magnetic resonance spectroscopy. This change in the position of the label can only occur by entry of [3-(13)C]glutamate into the tricarboxylic acid (TCA) cycle, conversion of labeled alpha-ketoglutarate to malate or oxaloacetate, malic enzyme-mediated decarboxylation of malate to pyruvate or phosphoenolpyruvate carboxykinase-mediated conversion of oxaloacetate to phosphoenolpyruvate and subsequent hydrolysis of the latter to pyruvate, and introduction of the labeled pyruvate into the TCA cycle, i.e., after exit of the carbon skeleton of pyruvate from the TCA cycle followed by re-entry of the same pyruvate molecules via acetyl CoA. In agreement with earlier observations, pyruvate recycling was demonstrated in astrocytes, indicating the ability of these cells to undertake complete oxidative degradation of glutamate. The recycled [4-(13)C]glutamate was not further converted to glutamine, showing compartmentation of astrocytic metabolism. Thus, absence of recycling into glutamine in the brain in vivo cannot be taken as indication that pyruvate recycling is absent in astrocytes. No recycling could be demonstrated in the cerebrocortical neurons. This is consistent with a previously demonstrated lack of incorporation of label from glutamate into lactate, and it also indicates that mitochondrial malic enzyme is not operational. Nor was there any indication of pyruvate recycling in the co-cultures. Although this may partly be due to more rapid depletion of glutamate in the co-cultures, this observation at the very least indicates that pyruvate recycling is not up-regulated in the neuronal-astrocytic co-cultures.
TL;DR: Using high-density filter-based cDNA microarrays, the expression of over 5000 genes in the dorsal hippocampus of rats treated with 12% ethanol or tap water for 15 months is analyzed to reveal some of the pathways involved in ethanol-induced pathophysiological changes.
Abstract: It is thought that changes in gene expression in the brain mediate chronic ethanol-induced complex behaviors such as tolerance, dependence, and sensitization, and also relate to ethanol-induced brain toxicity. Using high-density filter-based cDNA microarrays (GeneFilters), we analyzed the expression of over 5000 genes in the dorsal hippocampus of rats treated with 12% ethanol or tap water for 15 months. Ethanol-induced changes in gene expression were particularly prominent in two groups of genes. One group consisted of oxidoreductases, including ceruloplasmin, uricase, branched-chain alpha-keto acid dehydrogenase, NADH ubiquinone oxidoreductase, P450, NAD+-isocitrate dehydrogenase, and cytochrome c oxidase, which may be related to ethanol-induced oxidative stress. The other group of genes included ADP-ribosylation factor, RAS related protein rab10, phosphatidylinositol 4-kinase, dynein-associated polypeptides, and dynamin-1, which seem to be involved in membrane trafficking. The results may reveal some of the pathways involved in ethanol-induced pathophysiological changes.
TL;DR: It is concluded that diabetes alters the molecular anatomy of the tight junctions in cerebral tissue by altering the content of select structural proteins.
Abstract: The endothelial or epithelial tight junctions create a barrier to diffusion of solutes. Since experimental diabetes mellitus is associated with considerable alterations in the blood-brain barrier (BBB), it is possible that specific tight junction proteins may be altered in diabetes. To test this hypothesis, Western and Northern blot analysis were carried out to measure the steady-state level of occludin and zonula occludens-one (ZO-1) proteins and mRNA levels in cerebral tissue of streptozotocin-induced diabetic rats and the results were compared to insulin treated diabetic rats and vehicle injected control rats. The cerebral occludin content in diabetic rats (115.4 ± 18.6 arbitrary units) was significantly reduced compared to insulin-treated diabetic rats (649.1 ± 141.2) or control rats (552.9 ± 82.9), p < 0.001. The ZO-1 content of cerebral tissue from diabetic rats (1240.6 ± 199.7 arbitrary units) was not significantly altered compared to controls (1310.8 ± 256.9). The cerebral occludin mRNA content relative to G3PDH mRNA was 1.35 ± 0.07 and 1.34 ± 0.19 in control and diabetic rats respectively. The cerebral ZO-1 mRNA content relative to G3PDH mRNA in diabetic and control rats was 1.135 ± 0.123 and 0.956 ± 0.038 respectively. These differences did not achieve statistical significance. It is concluded that diabetes alters the molecular anatomy of the tight junctions in cerebral tissue by altering the content of select structural proteins.
TL;DR: The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism.
Abstract: Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D1: SCH 23390, D2: eticlopride), and NMDA glutamatergic (MK 801) and GABAB (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABAB (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D1 (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.
TL;DR: The results suggest that restraint stress differentially affects the activity of central dopaminergic and serotonergic neurons, and this may be related to the effects observed in eating behavior.
Abstract: Monoaminergic systems are important modulators of the responses to stress. Stress may influence feeding behavior, and the involvement of monoamines in the control of food intake is well recognized. We investigated the effects induced by chronic-restraint stress, 1 h a day, for 40 days, on eating behavior and on monoamines in distinct brain structures. Increased consumption of sweet pellets, and not of peanuts, was observed. Dopamine (DA), serotonin (5–HT), and their metabolites were measured by HPLC-EC. After chronic restraint, the results observed were decreased 5–HT in hippocampus, with increased 5–HIAA/5–HT; decreased 5–HIAA levels in cortex; reduction in DA in hippocampus, and increased levels in amygdala and hypothalamus; HVA increased in cortex, as well as HVA/DA ratio, while DOPAC/DA decreased. HVA decreased in hypothalamus, as well as HVA/DA, and DOPAC/DA and HVA/DA decreased in the amygdala. These results suggest that restraint stress differentially affects the activity of central dopaminergic and serotonergic neurons, and this may be related to the effects observed in eating behavior.
TL;DR: This paper calculates that 1.4% of total brain ATP consumption is consumed for the de novo synthesis of ether phospholipids and that another 5% is allocated to the phosphatidylinositide cycle.
Abstract: Until recently, brain phospholipid metabolism was thought to consume only 2% of the ATP consumed by the mammalian brain as a whole. In this paper, however, we calculate that 1.4% of total brain ATP consumption is consumed for the de novo synthesis of ether phospholipids and that another 5% is allocated to the phosphatidylinositide cycle. When added to previous estimates that fatty acid recycling within brain phospholipids and maintenance of membrane lipid asymmetries of acidic phospholipids consume, respectively, 5% and 8% of net brain ATP consumption, it appears that phospholipid metabolism can consume up to 20% of net brain ATP consumption. This new estimate is consistent with recent evidence that phospholipids actively participate in brain signaling and membrane remodeling, among other processes.
TL;DR: A more general theory that O-acetylated sialic acids in gangliosides are a universal marker for growing cells and tissues is delineated.
Abstract: Gangliosides, carrying an O-acetylated sialic acid in their carbohydrate moiety, are often found in growing and developing tissues, especially of neuro-ectodermal origin. The most prominent one is 9-O-Ac-GD3, which is considered as an oncofetal marker in animal and human tumors like neuronal tumors, melanoma, basalioma or breast cancer, as well as in psoriatic lesions. Also other gangliosides like GD2 or GT3 were found to be O-acetylated in their terminal sialic acid. In this review we are summarising the occurrence of such gangliosides in normal and transformed tissues and delineate a more general theory that O-acetylated sialic acids in gangliosides are a universal marker for growing cells and tissues.
TL;DR: It is proposed that the neuroprotective action of Ebselen can be related, in addition to its glutathione peroxidase-like and antilipoperoxidative activity, to a direct interaction with the glutamatergic system by reducing Kï-evoked glutamate release.
Abstract: We investigated effects of Ebselen, diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 on [3H]glutamate uptake and release by brain synaptosomes Ebselen after acute exposure inhibited K+-stimulated [3H]glutamate release by brain synaptosomes (PhSe)2 and (PhTe)2 did not change [3H]glutamate release by brain synaptosomes Ebselen, (PhSe)2 and (PhTe)2 had no significantly effects on [3H]glutamate uptake after acute exposure In vitro, Ebselen (100 μM) inhibited [3H]glutamate release and uptake (PhSe)2 had no significant effect, while (PhTe)2 (100 μM) inhibited [3H]glutamate uptake by brain synaptosomes In vitro, (PhSe)2, (PhTe)2 and Ebselen caused a significant inhibition of [3H]glutamate uptake by brain synaptic vesicles in vitro The results demonstrated that organochalcogenides have a rather complex effect on glutamate homeostasis depending on the compound and the schedule of exposition We propose that the neuroprotective action of Ebselen can be related, in addition to its glutathione peroxidase-like and antilipoperoxidative activity, to a direct interaction with the glutamatergic system by reducing Ki-evoked glutamate release
TL;DR: ALCAR attenuated oxidative stress and cell death induced by Abeta neurotoxicity, suggesting ALCAR may mediate its protective effect by buffering oxidative Stress and maintaining ATP levels.
Abstract: Acetyl-l-carnitine (ALCAR), normally produced in mitochondria, is a precursor of acetyl-CoA in the tricarboxylic (TCA) cycle. Since mitochondrial compromise and ATP depletion have been considered to play a role in neuronal degeneration in Alzheimer's disease (AD), we examined whether ALCAR attenuated oxidative stress and/or ATP depletion after exposure of cells to beta-amyloid (Abeta), a neurotoxic peptide that accumulates in AD brain. Differentiated SH-SY-5Y human neuroblastoma cells were exposed for 2–24 h to 20 μM Abeta in the presence and absence of 50 μM ALCAR. ALCAR attenuated oxidative stress and cell death induced by Abeta neurotoxicity. Abeta depleted ATP levels, suggesting Abeta may induce neurotoxicity in part by compromising neuronal energy. ALCAR prevented ATP depletion; therefore, ALCAR may mediate its protective effect by buffering oxidative stress and maintaining ATP levels.
TL;DR: The dynamics of cortical F-actin is controlled by two mechanisms: a) stimulation-induced Ca2+ entry and scinderin activation and b) protein kinase C (PKC) activation and MARCKS phosphorylation as demonstrated here by experiments with recombinant proteins, antisense olygodeoxynucleotides and vector mediated transient expressions.
Abstract: Chromaffin cells possess a mesh of filamentous actin underneath the plasma membrane which acts as a barrier to the chromaffin vesicles access to exocytotic sites. Disassembly of cortical F-actin in response to stimulation allows the movement of vesicles from the reserve pool to the release-ready vesicle pool and, therefore, to exocytotic sites. The dynamics of cortical F-actin is controlled by two mechanisms: a) stimulation-induced Ca2+ entry and scinderin activation and b) protein kinase C (PKC) activation and MARCKS phosphorylation as demonstrated here by experiments with recombinant proteins, antisense olygodeoxynucleotides and vector mediated transient expressions. Under physiological conditions (i.e., cholinergic receptor stimulation followed by Ca2+ entry), mechanism (a) is the most important for the control of cortical F-actin network whereas when Ca2+ is released from intracellular stores (i.e., histamine stimulation) cortical F-actin is regulated mainly by mechanism b.
TL;DR: Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.
Abstract: Memory retrieval is a fundamental component or stage of memory processing. In fact, retrieval is the only possible measure of memory. The ability to recall past events is a major determinant of survival strategies in all species and is of paramount importance in determining our uniqueness as individuals. Most biological studies of memory using brain lesion and/or gene manipulation techniques cannot distinguish between effects on the molecular mechanisms of the encoding or consolidation of memories and those responsible for their retrieval from storage. Here we examine recent findings indicating the major molecular steps involved in memory retrieval in selected brain regions of the mammalian brain. Together the findings strongly suggest that memory formation and retrieval may share some molecular mechanisms in the hippocampus and that retrieval initiates extinction requiring activation of several signaling cascades and protein synthesis.
TL;DR: The results suggest that neuronal apoptosis may be induced by ER stress through a NF-κB and caspase related pathway.
Abstract: Apoptosis is a conserved active cellular mechanism occurring under a range of physiological and pathological conditions. In the nervous system, apoptosis plays crucial roles in normal development and neuronal degenerating diseases. Various deleterious conditions, including accumulation of the mutant proteins in the endoplasmic reticulum (ER) and inhibition of ER to Golgi transport of proteins, may result in apoptosis. In this study, we examined the downstream events of apoptosis in differentiated PC 12 cells under ER stress induced by brefeldin A, an inhibitor of ER to Golgi protein transport. Activation of NF-kappaB and degradation of I-kappaB were observed within 2 hours, followed by up-regulation of GRP78 protein level in treated cells. Caspase-12 only appeared around 24 hours after brefeldin A treatment, coincident with cell nuclei fragmentation. These results suggest that neuronal apoptosis may be induced by ER stress through a NF-kappaB and caspase related pathway.