bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amphetamine‐evoked c‐fos mRNA expression in the caudate‐putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context
Authors: Ferguson Susan M. , Norton Camille S. , Watson Stanley J. , Akil Huda , Robinson Terry E. 
Published: June 2003

AbstractDopamine (DA) and glutamate neurotransmission is thought to be critical for psychostimulant drugs to induce immediate early genes (IEGs) in the caudate‐putamen (CPu). We report here, however, that the ability of DA and glutamate NMDA receptor antagonists to attenuate amphetamine‐evoked c‐fos mRNA expression in the CPu depends on environmental context. When given in the home cage, amphetamine induced c‐fos mRNA expression predominately in preprodynorphin and preprotachykinin mRNA‐containing neurons (Dyn‐SP+ cells) in the CPu. In this condition, all of the D1R, D2R and NMDAR antagonists tested dose‐dependently decreased c‐fos expression in Dyn‐SP+ cells. When given in a novel environment, amphetamine induced c‐fos mRNA in both Dyn‐SP+ and preproenkephalin mRNA‐containing neurons (Enk+ cells). In this condition, D1R and non‐selective NMDAR antagonists dose‐dependently decreased c‐fos expression in Dyn‐SP+ cells, but neither D2R nor NR2B‐selective NMDAR antagonists had no effect. Furthermore, amphetamine‐evoked c‐fos expression in Enk+ cells was most sensitive to DAR and NMDAR antagonism; the lowest dose of every antagonist tested significantly decreased c‐fos expression only in these cells. Finally, novelty‐stress also induced c‐fos expression in both Dyn‐SP+ and Enk+ cells, and this was relatively resistant to all but D1R antagonists. We suggest that the mechanism(s) by which amphetamine evokes c‐fos expression in the CPu varies depending on the stimulus (amphetamine vs. stress), the striatal cell population engaged (Dyn‐SP+ vs. Enk+ cells), and environmental context (home vs. novel cage).
Subcellular distributions of rat CaM kinase phosphatase N and other members of the CaM kinase regulatory system
Authors: Kitani Takako , Okuno Sachiko , Takeuchi Masayuki , Fujisawa Hitoshi 
Published: June 2003

AbstractCa2+/Calmodulin‐dependent protein kinase (CaM kinase) regulatory system is composed of multifunctional CaM kinases such as CaM kinases IV and I, upstream CaM kinases such as CaM kinase kinases α and β, which activate multifunctional CaM kinases, and CaM kinase phosphatases such as CaM kinase phosphatase and CaM kinase phosphatase N, which deactivate the activated multifunctional CaM kinases. To understand the combinations of CaM kinases I and IV, CaM kinase kinases α and β, and CaM kinase phosphatases, the locations of the enzymes in the cell were examined by immunocytochemical studies of cultured cells. The results indicate that CaM kinase I, CaM kinase kinase β, and CaM kinase phosphatase occur in the cytoplasm and that CaM kinase IV, CaM kinase kinase α (and CaM kinase kinase β in some cell types and tissues), and CaM kinase phosphatase N occur inside the cellular nucleus, suggesting that there are at least two different sets of CaM kinase regulatory systems, one consisting of CaM kinase I, CaM kinase kinase β, and CaM kinase phosphatase in the cytoplasm and the other consisting of CaM kinase IV, CaM kinase kinase α (and CaM kinase kinase β in some cell types and tissues), and CaM kinase phosphatase N in the nucleus.
Distribution, levels, and activation of MEK1 in Alzheimer's disease
Authors: Zhu Xiongwei , Sun Zheng , Lee Hyoung‐gon , Siedlak Sandra L. , Perry George , Smith Mark A. 
Published: June 2003

AbstractExtracellular‐signal‐regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen‐activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age‐matched control cases, increased levels of activated phospho‐MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V–VI). The considerable overlap between MEK1 and its downstream effector, phospho‐ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho‐MEK1 was a prominent feature in both mild AD cases (Braak stage III–IV) and control cases with limited pathology (Braak stage I–II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino‐terminus, we suspect that the apparent nuclear accumulation of phospho‐MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho‐MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.
The influence of brain inflammation upon neuronal adenosine A2Breceptors
Authors: Rosi Susanna , McGann Kristin , Hauss‐Wegrzyniak Beatrice , Wenk Gary L. 
Published: June 2003

AbstractAlzheimer's disease (AD) is associated with glial activation and increased levels of pro‐inflammatory cytokines. Epidemiological results suggest that anti‐inflammatory therapies can slow the onset of AD. Adenosine, acting at type‐2 receptors, is an effective endogenous anti‐inflammatory agent that can modulate inflammation both in the periphery and the brain. We investigated changes in the expression of adenosine type‐2B (A2B) receptors and a related intracellular second messenger during chronic brain inflammation and following treatment with the non‐steroidal anti‐inflammatory drug flurbiprofen and its nitric oxide (NO)‐donating derivative, HCT1026. Chronic infusion of lipopolysaccharide (LPS) into the 4th ventricle of young rats induced brain inflammation that was associated with microglial activation and reduced neuronal immunoreactivity for adenosine A2Breceptors in the cortex. Daily administration of HCT1026, but not flurbiprofen, reduced microglial activation, prevented the down‐regulation of A2Breceptors and elevated tissue levels of cAMP. The results suggest that a therapy using an NO‐releasing NSAID might significantly attenuate the processes that drive the pathology associated with AD and that this process may involve the activation of adenosine A2Breceptors.
Gene expression in human neural stem cells: effects of leukemia inhibitory factor
Authors: Wright Lynda S. , Li Jiang , Caldwell Maeve A. , Wallace Kyle , Johnson Jeffrey A. , Svendsen Clive N. 
Published: June 2003

AbstractHuman neural precursor cells grown in culture provide a source of tissue for drug screening, developmental studies and cell therapy. However, mechanisms underlying their growth and differentiation are poorly understood. We show that epidermal growth factor (EGF) responsive precursors derived from the developing human cortex undergo senescence after 30–40 population doublings. Leukemia inhibitory factor (LIF) increased overall expansion rates, prevented senescence and allowed the growth of a long‐term self renewing neural stem cell (ltNSCctx) for up to 110 population doublings. We established basal gene expression in ltNSCctx using Affymetrix oligonucleotide microarrays that delineated specific members of important growth factor and signaling families consistently expressed across three separate lines. Following LIF withdrawal, 200 genes showed significant decreases. Protein analysis confirmed LIF‐regulated expression of glial fibrillary acidic protein, CD44, and major histocompatibility complex I. This study provides the first molecular profile of human ltNSCctx cultures capable of long‐term self renewal, and reveals specific sets of genes that are directly or indirectly regulated by LIF.
Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3‐kinase (PI3) kinase‐dependent manner in Neuro2a cells
Authors: Van Der Heide L. P. , Hoekman M. F. , Biessels G. J. , Gispen W. H. 
Published: June 2003

AbstractInsulin signalling is well studied in peripheral tissue, but not in neuronal tissue. To gain more insight into neuronal insulin signalling we examined protein kinase B (PKB) and extracellular regulated kinase 1 and 2 (ERK1/2) regulation in serum‐deprived Neuro2a cells. Insulin phosphorylated PKB in a dose‐dependent manner but reduced phosphorylation of ERK1/2. Both processes were phosphatidylinositol 3‐kinase (PI3K) dependent. Interestingly, blockade of PI3K in combination with insulin induced phosphorylation of ERK1/2. The phosphorylation of ERK1/2 could be blocked with a specific inhibitor of mitogen‐activated protein/ERK kinase (MEK), suggesting that it was mediated through the highly conserved Ras–Raf–MEK–ERK1/2 pathway. Prolonged exposure to high concentrations of insulin resulted in a desensitized PI3K–PKB route. The insulin‐induced inhibition of ERK1/2 phosphorylation was also diminished when the PI3K–PKB route was desensitized. Blockade of PI3K in combination with insulin, however, still resulted in an unaltered MEK‐dependent phosphorylation of ERK1/2. We conclude that PI3K is an important integrator of insulin signalling in Neuro2a cells as it regulates activation of PKB and inhibition of ERK1/2, and is sensitive to the duration of the insulin stimulus.
Secretion of interleukin‐1β by astrocytes mediates endothelin‐1 and tumour necrosis factor‐α effects on human brain microvascular endothelial cell permeability
Authors: Didier Nathalie , Romero Ignacio A. , Créminon Christophe , Wijkhuisen Anne , Grassi Jacques , Mabondzo Aloïse 
Published: June 2003

AbstractEvidence suggests that endothelin‐1 (ET‐1) plays an essential role in brain inflammation. However, whether ET‐1 contributes directly to blood–brain barrier (BBB) breakdown remains to be elucidated. Using an in vitro BBB model consisting of co‐cultures of human primary astrocytes and brain microvascular endothelial cells (BMVECs), we first investigated the expression of ET‐1 by BMVECs upon stimulation with tumour necrosis factor (TNF)‐α, which plays an essential role in the induction and synthesis of ET‐1 during systemic inflammatory responses. Increased ET‐1 mRNA was detected in the human BMVECs 24 h after TNF‐α treatment. This was correlated with an increase in ET‐1 levels in the culture medium, as determined by sandwich immunoassay. Both TNF‐α and ET‐1 increased the permeability of human BMVECs to a paracellular tracer, sucrose, but only in the presence of astrocytes. The increase in BMVEC permeability by TNF‐α was partially prevented by antibody neutralization of ET‐1 and completely by monoclonal antibody against IL‐1β. Concomitantly, TNF‐α induced IL‐1β mRNA expression by astrocytes in co‐culture and this effect was partially prevented by ET‐1 antibody neutralization. In parallel experiments, treatment of human primary astrocytes in single cultures with ET‐1 for 24 h induced IL‐1β mRNA synthesis and IL‐1β protein secretion in the cell culture supernatant. Taken together, these results provide evidence for paracrine actions involving ET‐1, TNF‐α and IL‐1β between human astrocytes and BMVECs, which may play a central role in BBB breakdown during CNS inflammation.
Mitogen and stress response kinase‐1 (MSK1) mediates excitotoxic induced death of hippocampal neurones
Authors: Hughes Jane P. , Staton Penny C. , Wilkinson Marc G. , Strijbos Paul J. L. M. , Skaper Stephen D. , Arthur J. Simon C. , Reith Alastair D. 
Published: June 2003

AbstractActivation of the mitogen‐activated protein kinase (MAPK/ERK) signal transduction pathway may mediate excitotoxic neuronal cell death in vitro and during ischemic brain injury in vivo. However, little is known, of the upstream regulation or downstream consequences of ERK activation under these conditions. Magnesium removal has been described to induce hyperexcitability and degeneration in cultured hippocampal neurones. Here, we show that neurotoxicity evoked by Mg2+ removal in primary hippocampal neurones stimulates ERK, but not p38, phosphorylation. Removal of Mg2+ also resulted in induction of the MAPK/ERK substrate mitogen‐ and stress‐response kinase 1 (MSK1) and induced phosphorylation of the MSK1 substrate, the transcription factor cAMP response element binding protein (CREB). Neuronal death and phosphorylation of components in this cascade were inhibited by the Raf inhibitor SB‐386023, by the MEK inhibitor U0126, or by the MSK1 inhibitors H89 and Ro318220. Importantly, this form of cell death was inhibited in hippocampal neurones cultured from MSK1–/– mice and inhibitors of Raf or MEK had no additive neuroprotective effect. Together, these data indicate that MSK1 is a physiological kinase for CREB and that this activity is an essential component of activity‐dependent neuronal cell death.
Pro‐apoptotic signaling in neuronal cells following iron and amyloid beta peptide neurotoxicity
Authors: Kuperstein Faina , Yavin Ephraim 
Published: June 2003

AbstractIn a previous report, we characterized several oxidative stress parameters during the course of amyloid beta (Aβ) peptide/Fe2+‐induced apoptotic death in neuronal cells. In extending these findings, we now report a marked decrease in protein kinase C (PKC) isoforms, reduced Akt serine/threonine kinase activity, Bcl 2‐associated death promoter (BAD) phosphorylation and enhanced p38 mitogen‐activated protein kinase (MAPK) and caspase‐9 and ‐3 activation, 12 h after addition of both 5 µm Aβ and 5 µm Fe2+. These activities reminiscent for a pro‐apoptotic cellular course were blocked in the presence of the iron chelator deferroxamine. Aβ alone, increased PKC isoform levels between three‐ and four‐fold after 12 h, enhanced Akt activity approximately eight‐fold and Ser136 BAD phosphorylation two‐fold, suggesting that by itself is not toxic. Fe2+ alone transiently enhanced p38 MAPK and caspase‐9 and ‐3 enzymes indicative for cell damage, but was not sufficient to cause cell death as previously indicated. GF, a PKC inhibitor or wortmannin, a blocker of the Akt pathway enhanced Aβ/Fe2+‐induced toxicity, while SB, a p38 MAPK inhibitor, prevented cell damage and apoptosis. These findings further support the hypothesis that metal ion chelation and inhibitors of pro‐apoptotic kinase cascades may be beneficial for Alzheimer's disease therapy.
Escalation of cocaine self‐administration does not depend on altered cocaine‐induced nucleus accumbens dopamine levels
Authors: Ahmed Serge H. , Lin Daniel , Koob George F. , Parsons Loren H. 
Published: June 2003

AbstractPrevious studies showed that prolonged access to cocaine or heroin self‐administration (long access, or LgA) produces an escalation in drug intake not observed with limited access to the drug (short access, or ShA). The present experiment employed in vivo microdialysis to test the role of alterations in drug pharmacokinetics and/or efficacy in increasing dopamine (DA) levels in the nucleus accumbens (NAcc) during cocaine intake escalation. In experiment 1, both ShA and LgA rats were challenged with passive intravenous administration of cocaine (0.125–1 mg/injection). Regardless of the doses tested, there was no difference between groups in the ability of cocaine to increase NAcc DA levels and no group differences in the temporal profile of dialysate cocaine levels. In experiment 2, cocaine and DA concentrations were measured during cocaine self‐administration. Self‐administration produced sustained increases of DA in the NAcc with LgA rats maintaining greater steady levels of DA (750% of baseline) than ShA rats (400% of baseline). The difference in the LgA versus ShA rats was not due to differences in the efficacy of cocaine to elevate DA levels, or in the rate of cocaine metabolism, but was directly related to the amount of self‐administered cocaine. These findings show that changes in cocaine efficacy or pharmacokinetics do not play a critical role in cocaine intake escalation.
Increased activin levels in cerebrospinal fluid of rabbits with bacterial meningitis are associated with activation of microglia
Authors: Michel Uwe , Gerber Joachim , E. O'Connor Anne , Bunkowski Stephanie , Brück Wolfgang , Nau Roland , Phillips David J. 
Published: June 2003

AbstractActivin, a member of the transforming growth factor superfamily, is upregulated in a number of inflammatory episodes such as septicemia and rheumatoid arthritis. In the CNS, activin has been predominantly assessed in terms of a neuroprotective role. In this report we characterized the activin response in the CNS in a rabbit model of meningitis. In normal animals, cerebrospinal fluid (CSF) activin levels were higher than those in serum, indicating an intracranial secretion of this cytokine. Following intracisternal inoculation with Streptococcus pneumoniae, activin in CSF was unchanged for the first 12 h and then rose progressively; levels were increased approximately 15‐fold within 24 h. Activin levels were correlated positively with CSF protein content and with the number of apoptotic neurons in the dentate gyrus. No apparent correlation was observed between CSF activin concentrations and bacterial titer, lactate concentrations or leukocyte density. Using immunohistochemistry, activin staining was localized to epithelial cells of the choroid plexus, cortical neurons and the CA3 region of the hippocampus, with similar staining intensities in both normal and meningitic brains. However, in meningitic brains there was also strong staining in activated microglia and infiltrating macrophages. Taken together, these results demonstrate that activin forms part of the CNS response to immune challenge and may be an important mediator to modulate inflammatory processes in the brain.
α‐Synuclein protects naive but not dbcAMP‐treated dopaminergic cell types from 1‐methyl‐4‐phenylpyridinium toxicity
Authors: Jensen Penny J. , Alter Benedict J. , O'Malley Karen L. 
Published: June 2003

AbstractThe pre‐synaptic protein, α‐synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that α‐synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism‐inducing drug 1‐methyl‐4‐phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6‐hydroxydopamine, hydrogen‐peroxide, or the β‐amyloid peptide, A‐β. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, α‐synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin‐induced activation of the creatine kinase/creatine phosphate system. Similarly, α‐synuclein protected cells from the complex I inhibitor rotenone and 3‐nitroproprionic acid, a complex II inhibitor. Wild‐type α‐synuclein‐mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP‐differentiated cells. These results suggest that the normal physiological role for α‐synuclein may change during development.
Characterization of a novel G‐protein coupled receptor from the parasitic nematode H. contortus with high affinity for serotonin
Authors: Smith Martin W. , Borts Tracy L. , Emkey Renee , Cook Carolyn A. , Wiggins Christina J. , Gutierrez Jesus A. 
Published: June 2003

AbstractThe neurotransmitter serotonin (5HT) has been shown to modulate mobility, feeding, egg‐laying, and defecation behaviors in the saprophytic nematode Caenorhabditis elegans. Although the effects of serotonin on these behaviors in parasitic nematodes is under study, little is known about the diversity, ontogeny, signaling, and pharmacology of serotonin receptors in these organisms. In an effort to increase our understanding of this system, we cloned and characterized a novel cDNA (5HT1Hc) from the parasitic nematode Haemonchus contortus that has high amino acid sequence homology with known G‐protein coupled 5HT1‐receptors from invertebrates and vertebrates. Transcript expression studies in four development stages (egg, L1/L2, L3, and adult) revealed the presence of the mRNA in the L1/L2, L3, and adult stages. Membranes from insect cells (Sf9) expressing the 5HT1Hc‐receptor cDNA displayed nanomolar binding affinity to serotonin and a unique pharmacological profile distinct from known invertebrate and mammalian 5HT‐receptors. Receptor signaling studies with mammalian AV12 cells expressing the 5HT1Hc‐receptor and the promiscuous G‐protein, Gα15, demonstrated dose‐dependent intracellular signals with serotonin acting as an agonist. Together, these studies describe a novel invertebrate 5HT‐receptor with high affinity for the indolealkylamine, serotonin, and pharmacological properties that do not conform to any known members of this superfamily of metabotropic receptors.
Selenium and selenoproteins in the brain and brain diseases
Authors: Chen Jun , Berry Marla J. 
Published: June 2003

AbstractOver the past three decades, selenium has been intensively investigated as an antioxidant trace element. It is widely distributed throughout the body, but is particularly well maintained in the brain, even upon prolonged dietary selenium deficiency. Changes in selenium concentration in blood and brain have been reported in Alzheimer's disease and brain tumors. The functions of selenium are believed to be carried out by selenoproteins, in which selenium is specifically incorporated as the amino acid, selenocysteine. Several selenoproteins are expressed in brain, but many questions remain about their roles in neuronal function. Glutathione peroxidase has been localized in glial cells, and its expression is increased surrounding the damaged area in Parkinson's disease and occlusive cerebrovascular disease, consistent with its protective role against oxidative damage. Selenoprotein P has been reported to possess antioxidant activities and the ability to promote neuronal cell survival. Recent studies in cell culture and gene knockout models support a function for selenoprotein P in delivery of selenium to the brain. mRNAs for other selenoproteins, including selenoprotein W, thioredoxin reductases, 15‐kDa selenoprotein and type 2 iodothyronine deiodinase, are also detected in the brain. Future research directions will surely unravel the important functions of this class of proteins in the brain.