bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholesterol‐dependent modulation of the toxicity of HIV‐1 coat protein gp120 in human neuroblastoma cells
Authors: Maccarrone Mauro , Navarra Michele , Catani Valeria , Corasaniti M. Tiziana , Bagetta Giacinto , Finazzi‐Agrò Alessandro 
Published: March 2003

AbstractThe human immunodeficiency virus type 1 (HIV‐1) coat glycoprotein gp120 binds to its (co)receptors and orchestrates cell entry by the direct fusion of viral and target cell membranes. Here, we modulated membrane fluidity of human neuroblastoma CHP100 cells by modulating their cholesterol content, and investigated the ability of gp120 to induce cell death in comparison with the untreated cells. We show that in normal CHP100 cells gp120 induces necrosis by: (i) increased cyclooxygenase and 5‐lipoxygenase activity, and metabolites generated thereof (prostaglandin E2 and leukotriene B4, respectively); (ii) increased membrane lipoperoxidation; and (iii) increased mitochondrial uncoupling. These events were triggered by a rapid increase in intracellular calcium, and in cholesterol‐depleted cells engaged CXCR4 chemokine receptors. The intracellular calcium chelator EGTA‐AM protected CHP100 cells almost completely against the toxic effects of gp120. However, gp120‐induced necrosis and related biochemical changes were negligible in cholesterol‐enriched, and significantly enhanced in cholesterol‐depleted, CHP100 cells exposed to the viral glycoprotein under the same experimental conditions. Taken together, these results suggest that membrane fluidity may control the neurotoxic effects of HIV‐1 glycoprotein gp120.
Proteasomal dysfunction induced by 4‐hydroxy‐2,3‐trans‐nonenal, an end‐product of lipid peroxidation: a mechanism contributing to neurodegeneration?
Authors: Hyun Dong‐Hoon , Lee Moon‐Hee , Halliwell Barry , Jenner Peter 
Published: March 2003

Abstract4‐Hydroxy‐2,3‐trans‐nonenal (HNE) is a neurotoxic unsaturated aldehyde end‐product of lipid peroxidation. The addition of HNE to NT‐2 and SK‐N‐MC cell lines induces apoptosis and we now investigated the time‐course of events occurring prior to apoptosis. Treatment of both NT‐2 and SK‐N‐MC cell lines with HNE led to HNE association with the proteasome, increased levels of protein carbonyls and ubiquitinated proteins, and decreased proteasomal function. There was also decreased metabolic activity, cytochrome c release and activation of caspase 3, followed by apoptotic changes including chromatin condensation, cell shrinkage and DNA fragmentation and laddering. Overexpression of mutant superoxide dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased proteasomal activities in the absence of HNE and accelerated the apoptosis induced by HNE. By contrast, overexpression of wild‐type superoxide dismutase 1 did not affect basal levels of proteasomal activity. The data suggest that accumulation of ubiquitinated proteins and impairment of proteasomal function are important events in HNE toxicity. We propose that the proteasomal system is a significant target of HNE neurotoxicity in a wide range of neurodegenerative diseases, especially if abnormal proteins are being expressed.
Circadian rhythmicity in dopamine content of mammalian retina: role of the photoreceptors
Authors: Doyle Susan E. , McIvor Wilson E. , Menaker Michael 
Published: March 2003

AbstractDopamine, the predominant retinal catecholamine, is a neurotransmitter and neuromodulator known to regulate light‐adaptive retinal processes. Because dopamine influences several rhythmic events in the retina it is also a candidate for a retinal circadian signal. Using high performance liquid chromatography (HPLC), we have tested whether dopamine and its breakdown products are rhythmic in Royal College of Surgeons (RCS) rats with normal and dystrophic retinas. In both normal and mutant animals entrained to a 12‐h light/12‐h dark cycle, we found robust daily rhythms of dopamine and its two major metabolites. To address circadian rhythmicity of dopamine content, rats were entrained to light/dark cycles and released into constant darkness, using the circadian rhythm of wheel‐running activity as a marker of each individual's circadian phase. Circadian rhythms of dopamine and metabolite content persisted in both wild type and retinally degenerate animals held for two weeks in constant darkness. Our results demonstrate for the first time clear circadian rhythms of dopamine content and turnover in a free‐running mammal, and suggest that rods and cones are not required for dopamine rhythmicity .
Dietary low linolenic acid compared with docosahexaenoic acid alter synaptic plasma membrane phospholipid fatty acid composition and sodium–potassium ATPase kinetics in developing rats
Authors: Bowen Raffick A. R. , Clandinin Michael T. 
Published: March 2003

AbstractThe objective of this study was to investigate if maternal dietary 20:4n‐6 arachidonic acid (AA) and 22:6n‐3 compared with adequate or low levels of 18:3n‐3 linolenic acid (LNA) increases synaptic plasma membrane (SPM) cholesterol and phospholipid content, phospholipid 20:4n‐6 and 22:6n‐3 content, and Na,K‐ATPase kinetics in rat pups at two and five weeks of age. At parturition, Sprague‐Dawley rats were fed semi‐purified diets containing either AA + docosahexaenoic acid (DHA), adequate LNA (control; 18:2n‐6 : 18:3n‐3 ratio of 7.1 : 1) or low LNA (18:2n‐6 : 18:3n‐39 ratio of 835 : 1). During the first two weeks of life, the rat pups received only their dams' milk. After weaning, pups received the same diet as their respective dams to five weeks of age. No significant difference was observed among rat pups fed the diet treatments for SPM cholesterol or total and individual phospholipid content at two and five weeks of age. Fatty acid analysis revealed that maternal dietary AA + DHA, compared with feeding the dams the control diet or the low LNA diet, increased 20:4n‐6 in phosphatidylserine and 22:6n‐3 content of SPM phospholipids. Rats fed dietary AA + DHA or the control diet exhibited a significantly increased Vmax for SPM Na,K‐ATPase. Diet treatment did not alter the Km (affinity) of SPM Na,K‐ATPase in rat pups at two and five weeks of age. It is concluded that dietary AA + DHA does not alter SPM cholesterol and phospholipid content but increases the 22:6n‐3 content of SPM phospholipids modulating activity of Na,K‐ATPase.
Kainate‐induced excitotoxicity is dependent upon extracellular potassium concentrations that regulate the activity of AMPA/KA type glutamate receptors
Authors: Ha Byeong Keun , Vicini Stefano , Rogers Richard C. , Bresnahan Jacqueline C. , Burry Richard W. , Beattie Michael S. 
Published: March 2003

AbstractIn addition to well‐known N‐methyl‐d‐aspartate (NMDA) receptor‐mediated excitotoxicity, recent studies suggest that non‐NMDA type ionotropic glutamate receptors are also important mediators of excitotoxic neuronal death, and that their functional expression can be regulated by the cellular environment. In this study, we used cerebellar granule cells (CGCs) in culture to investigate kainate (KA)‐induced excitotoxicity. Although previous reports indicated that KA induces apoptosis of CGCs in culture, no KA‐induced excitotoxic cell death was observed in CGCs treated with KA when cells were maintained in high potassium media (24 mm K+). In contrast, when mature CGCs were shifted into low potassium media (3 mm K+), KA produced significant excitotoxicity. In electrophysiological studies, the KA‐induced inward current density was significantly elevated in CGCs shifted into low K+ media compared with those maintained in high K+ media. Non‐desensitizing aspects of KA currents observed in this study suggest that these responses were mediated by AMPA rather than KA receptors. In immunofluorescence studies, the surface expression of GluR1 subunits increased when mature CGCs were shifted into a low K+ environment. This study suggests that KA‐induced excitotoxicity in mature CGCs is dependent upon the extracellular potassium concentration, which modulates functional expression and excitability of AMPA/KA receptors.
Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia
Authors: Raghavendra Rao Vemuganti L. , Bowen Kellie K. , Dhodda Vinay K. , Song Guoqing , Franklin James L. , Gavva Narender R. , Dempsey Robert J. 
Published: March 2003

AbstractIdentification of novel modulators of ischemic neuronal death helps in developing new strategies to prevent the stroke‐induced neurological dysfunction. Hence, the present study evaluated the gene expression changes in rat cerebral cortex at 6 and 24 h of reperfusion following transient middle cerebral artery occlusion (MCAO) by GeneChip® analysis. Transient MCAO resulted in selective increased mRNA levels of genes involved in stress, inflammation, transcription and plasticity, and decreased mRNA levels of genes which control neurotransmitter function and ionic balance. In addition to a number of established ischemia‐related genes, many genes not previously implicated in transient focal ischemia‐induced brain damage [suppressor of cytokine signaling (SOCS)‐3, cAMP responsive element modulator (CREM), cytosolic retinol binding protein (CRBP), silencer factor‐B, survival motor neuron (SMN), interferon‐γ regulatory factor‐1 (IRF‐1), galanin, neurotrimin, proteasome subunit RC8, synaptosomal‐associated protein (SNAP)‐25 A and B, synapsin 1a, neurexin 1‐β, ras‐related rab3, vesicular GABA transporter (VGAT), digoxin carrier protein, neuronal calcium sensor‐1 and neurodap] were observed to be altered in the ischemic cortex. Real‐time PCR confirmed the GeneChip® results for several of these transcripts. SOCS‐3 is a gene up‐regulated after ischemia which modulates inflammation by controlling cytokine levels. Antisense knockdown of ischemia‐induced SOCS‐3 protein expression exacerbated transient MCAO‐induced infarct volume assigning a neuroprotective role to SOCS‐3, a gene not heretofore implicated in ischemic neuronal damage.
Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species
Authors: Qin Liya , Liu Yuxin , Cooper Cynthia , Liu Bin , Wilson Belinda , Hong Jau‐Shyong 
Published: March 2003

AbstractThe purpose of this study was to assess and compare the toxicity of β‐amyloid (Aβ) on primary cortical and mesencephalic neurons cultured with and without microglia in order to determine the mechanism underlying microglia‐mediated Aβ‐induced neurotoxicity. Incubation of cortical or mesencephalic neuron‐enriched and mixed neuron–glia cultures with Aβ(1–42) over the concentration range 0.1–6.0 μm caused concentration‐dependent neurotoxicity. High concentrations of Aβ (6.0 μm for cortex and 1.5–2.0 μm for mesencephalon) directly injured neurons in neuron‐enriched cultures. In contrast, lower concentrations of Aβ (1.0–3.0 μm for cortex and 0.25–1.0 μm for mesencephalon) caused significant neurotoxicity in mixed neuron–glia cultures, but not in neuron‐ enriched cultures. Several lines of evidence indicated that microglia mediated the potentiated neurotoxicity of Aβ, including the observations that low concentrations of Aβ activated microglia morphologically in neuron–glia cultures and that addition of microglia to cortical neuron–glia cultures enhanced Aβ‐induced neurotoxicity. To search for the mechanism underlying the microglia‐mediated effects, several proinflammatory factors were examined in neuron–glia cultures. Low doses of Aβ significantly increased the production of superoxide anions, but not of tumor necrosis factor‐α, interleukin‐1β or nitric oxide. Catalase and superoxide dismutase significantly protected neurons from Aβ toxicity in the presence of microglia. Inhibition of NADPH oxidase activity by diphenyleneiodonium also prevented Aβ‐induced neurotoxicity in neuron–glia mixed cultures. The role of NADPH oxidase‐generated superoxide in mediating Aβ‐induced neurotoxicity was further substantiated by a study which showed that Aβ caused less of a decrease in dopamine uptake in mesencephalic neuron–glia cultures from NADPH oxidase‐deficient mutant mice than in that from wild‐type controls. This study demonstrates that one of the mechanisms by which microglia can enhance the neurotoxicity of Aβ is via the production of reactive oxygen species.
Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann–Pick C1‐deficient neurons
Authors: Karten Barbara , Vance Dennis E. , Campenot Robert B. , Vance Jean E. 
Published: March 2003

AbstractNiemann–Pick type‐C (NPC) disease is characterized by a progressive loss of neurons and an accumulation of unesterified cholesterol within the endocytic pathway. Unlike other tissues, however, NPC1‐deficient brains do not accumulate cholesterol but whether or not NPC1‐deficient neurons accumulate cholesterol is not clear. Therefore, as most studies on cholesterol homeostasis in NPC1‐deficient cells have been performed in fibroblasts we have investigated cholesterol homeostasis in cultured murine sympathetic neurons lacking functional NPC1. These neurons did not display obvious abnormalities in growth or morphology and appeared to respond normally to nerve growth factor. Filipin staining revealed numerous cholesterol‐filled endosomes/lysosomes in NPC1‐deficient neurons and the mass of cholesterol in cell bodies was greater than in wild‐type neurons. Surprisingly, however, the cholesterol content of NPC1‐deficient and wild‐type neurons as a whole was the same. This apparent paradox was resolved when the cholesterol content of NPC1‐deficient distal axons was found to be less than of wild‐type axons. Cholesterol sequestration in cell bodies did not depend on exogenously supplied cholesterol since the cholesterol accumulated before birth and did not disperse when neurons were cultured without exogenous cholesterol. The altered cholesterol distribution between cell bodies and axons suggests that transport of cholesterol, particularly that synthesized endogenously, from cell bodies to distal axons is impaired in NPC1‐deficient neurons.
Heterogeneous expression of the triggering receptor expressed on myeloid cells‐2 on adult murine microglia
Authors: Schmid Christoph D. , Sautkulis Lauren N. , Danielson Patria E. , Cooper Judith , Hasel Karl W. , Hilbush Brian S. , Sutcliffe J. Gregor , Carson Monica J. 
Published: March 2003

AbstractMicroglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA® to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells‐2 (TREM‐2) was among the mRNAs identified as being expressed by unactivated microglia, but down‐regulated by lipopolysaccharide/interferon γ. In the healthy CNS, not all microglia expressed TREM‐2. Microglial expression of TREM‐2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood–brain barrier had the lowest percentages of TREM‐2‐ expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM‐2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) regional variations in TREM‐2 expression may contribute to the varying sensitivities of different brain regions to similar pathological signals.
Circadian regulation of a transcription factor, ApC/EBP, in the eye of Aplysia californica
Authors: Hattar Samer , Lyons Lisa C. , Dryer Laurence , Eskin Arnold 
Published: March 2003

AbstractThe transcription factor, ApC/EBP (Aplysia CCAAT enhancer‐binding protein) is an immediate early gene that is rapidly induced by serotonin and the cAMP signaling pathway. ApC/EBP acts as an important link following the activation of protein kinase A (PKA) in the consolidation of long‐term memory in Aplysia californica. In this study, we report that levels of ApC/EBP mRNA in the eye of Aplysia are modulated by serotonin or light. These responses of ApC/EBP to serotonin and light are mimicked by analogs of cAMP and cGMP. Expression of ApC/EBP in the eye is also under the control of the circadian oscillator with circadian rhythms of ApC/EBP mRNA present under constant dark conditions. Therefore, ApC/EBP is a candidate gene for a circadian transcription factor to mediate circadian responses activated by the cAMP and cGMP second messenger signaling pathways.
Up‐regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B‐dependent mechanisms
Authors: Rumajogee Prakasham , Madeira Alexandra , Vergé Daniel , Hamon Michel , Miquel Marie‐Christine 
Published: March 2003

AbstractThe effects of brain‐derived neurotrophic factor (BDNF) and cAMP on the neuronal serotoninergic phenotype were studied in primary cultures of E14 rat embryonic rostral raphe. Short treatments (for 18 h) with BDNF or dibutyryl‐cAMP induced an almost two‐fold increase in the number of serotoninergic neurones and a dramatic extension and ramification of their neurites. These changes were associated with marked increases in the levels of mRNAs encoding the serotonin transporter, the 5‐HT1A and 5‐HT1B receptors and the BDNF receptor tyrosine kinase B (TrkB). Concomitant blockade of tyrosine kinases by genistein suppressed all the up‐regulating effects of BDNF and cAMP on 5‐hydroxytryptamine (5‐HT) neurones. These findings suggest that an auto‐amplifying mechanism underlies the promoting effect of BDNF on the differentiation of serotoninergic neurones through TrkB activation, which is also triggered by cAMP.
Age‐dependent myelin degeneration and proteolysis of oligodendrocyte proteins is associated with the activation of calpain‐1 in the rhesus monkey
Authors: Sloane J. A. , Hinman J. D. , Lubonia M. , Hollander W. , Abraham C. R. 
Published: March 2003

AbstractMyelin provides important insulating properties to axons allowing for propagation of action potentials over large distances at high velocity. Disruption of the myelin sheath could therefore contribute to cognitive impairment, such as that observed during the normal aging process. In the present study, age‐related changes in myelin, myelin proteins and oligodendrocyte proteins were assessed in relationship to calpain‐1 expression and cognition in the rhesus monkey. Isolation of myelin fractions from brain white matter revealed that as the content of the intact myelin fraction decreased with age, there was a corresponding increase in the floating or degraded myelin fraction, suggesting an increased breakdown of intact myelin with age. Of the myelin proteins examined, only the myelin‐associated glycoprotein decreased with age. Levels of the oligodendrocyte‐specific proteins 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase (CNPase) and myelin/oligodendrocyte‐specific protein (MOSP) increased dramatically in white matter homogenates and myelin with age. Age‐related increases in degraded CNPase also were demonstrable in white matter in association with increases in activated calpain‐1. Degraded CNPase was also detectable in myelin fractions, with only the floating fraction containing activated calpain‐1. The increases in the activated enzyme in white matter were much greater than those found in myelin fractions suggesting a source other than the myelin membrane for the marked overexpression of activated calpain‐1 with age. In addition, CNPase was demonstrated to be a substrate for calpain in vitro. In summary, changes in myelin and oligodendrocyte proteins occur with age, and they appear to have a significant relationship to cognitive impairment. The overexpression of CNPase and MOSP suggests new formation of myelin by oligodendrocytes, which may occur in response to myelin degradation and injury caused by proteolytic enzymes such as calpain.
Regulation of c‐Jun N‐terminal kinase, p38 kinase and AP‐1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection
Authors: Chen Ren‐Wu , Qin Zheng‐Hong , Ren Ming , Kanai Hirohiko , Chalecka‐Franaszek Elzbieta , Leeds Peter , Chuang De‐Maw 
Published: March 2003

AbstractIn rat cerebellar granule cells, glutamate induced rapid activation of c‐Jun N‐terminal kinase (JNK) and p38 kinase to phosphorylate c‐Jun (at Ser63) and p53 (at Ser15), respectively, and a subsequent marked increase in activator protein‐1 (AP‐1) binding that preceded apoptotic death. These glutamate‐induced effects and apoptosis could largely be prevented by long‐term (7 days) pretreatment with 0.5–2 mm lithium, an antibipolar drug. Glutamate's actions could also be prevented by known blockers of this pathway, MK‐801 (an NMDA receptor blocker), SB 203580 (a p38 kinase inhibitor) and curcumin (an AP‐1 binding inhibitor). The concentration‐ and time‐dependent suppression of glutamate's effects by lithium and curcumin correlated well with their neuroprotective effects. These results suggest a prominent role of JNK and p38, as well as their downstream AP‐1 binding activation and p53 phosphorylation in mediating glutamate excitotoxicity. Moreover, the neuroprotective effects of lithium are mediated, at least in part, by suppressing NMDA receptor‐mediated activation of the mitogen‐activated protein kinase pathway.
THIS ARTICLE HAS BEEN RETRACTED Activation of capsaicin‐sensitive primary sensory neurones induces anandamide production and release
Authors: Ahluwalia J. , Yaqoob Mohammed , Urban Laszlo , Bevan Stuart , Nagy Istvan 
Published: March 2003

AbstractThe inhibitory cannabinoid 1 receptor and the excitatory vanilloid receptor 1, both of which are responsive to the endogenous ligand anandamide, are co‐expressed on a subpopulation of primary sensory neurones. We report that activation of the cannabinoid 1 receptor/vanilloid receptor 1‐co‐expressing primary sensory neurones induces the production and release of anandamide. Application of capsaicin (3 nm−1 µm) to cultured primary sensory neurones evoked calcitonin gene‐related peptide release, which was significantly increased by the selective cannabinoid 1 receptor antagonist, SR141716A (200 nm). Mass spectrometric analyses of the extracellular solution revealed that exposure to capsaicin (10 nm or 100 nm) enhanced the anandamide concentration of the medium from less then 0.05 pmol/µL to more then 2 pmol/µL. Depolarization of the neurones with 50 mm KCl also enhanced the anandamide content of the buffer. Both the capsaicin‐ and KCl‐induced anandamide release depended on extracellular Ca2+. Prolonged treatment of the cultures with capsaicin (10 µm) reduced both the capsaicin‐ and KCl‐induced anandamide release. These findings indicate that activation of capsaicin‐sensitive primary sensory neurones evokes anandamide production and release, and that anandamide might be a key endogenous regulator of the excitability of these neurones.