bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nogo‐66 and myelin‐associated glycoprotein (MAG) inhibit the adhesion and migration of Nogo‐66 receptor expressing human glioma cells
Authors: Liao Hong , Duka Tetyana , Teng Felicia Y. H. , Sun Li , Bu Wen‐yu , Ahmed Sohail , Tang Bor Luen , Xiao Zhi‐Cheng 
Published: August 2004

AbstractMalignant gliomas are common and aggressive brain tumours associated with significant morbidity and mortality. We showed in this report that substratum adherence and migration by human U87MG glioma cells in culture were significantly attenuated by the extracellular domains of Nogo‐A (Nogo‐66) and the myelin‐associated glycoprotein (MAG). U87MG cells contained significant amounts of endogenous Nogo‐66 receptor (NgR), and treatment of the cells with phosphatidylinositol‐specific phospholipase C (PI‐PLC) or NgR antibodies resulted in an increase in their ability to adhere to, or migrate through, Nogo‐66‐ and MAG‐coated substrates. Nogo‐66 and MAG may therefore modulate glioma growth and migration by acting through the NgR, a phenomenon that has potential therapeutic implications.
Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons
Authors: Hamada Miho , Higashi Hideho , Nairn Angus C. , Greengard Paul , Nishi Akinori 
Published: August 2004

AbstractNicotine, acting on nicotinic acetylcholine receptors (nAChRs) expressed at pre‐synaptic dopaminergic terminals, has been shown to stimulate the release of dopamine in the neostriatum. However, the molecular consequences of pre‐synaptic nAChR activation in post‐synaptic neostriatal neurons are not clearly understood. Here, we investigated the effect of nAChR activation on dopaminergic signaling in medium spiny neurons by measuring phosphorylated DARPP‐32 (dopamine‐ and cAMP‐regulated phosphoprotein of Mr 32 kDa) at Thr34 (the PKA‐site) in mouse neostriatal slices. Nicotine produced dose‐dependent responses, with a low concentration (1 µm) causing a sustained decrease in DARPP‐32 Thr34 phosphorylation and a high concentration (100 µm) causing a transient increase in DARPP‐32 Thr34 phosphorylation. Depending on the concentration of nicotine, either dopamine D2 or D1 receptor signaling was predominantly activated. Nicotine at a low concentration (1 µm) activated dopamine D2 receptor signaling in striatopallidal/indirect pathway neurons, likely by activating α4β2* nAChRs at dopaminergic terminals. Nicotine at a high concentration (100 µm) activated dopamine D1 receptor signaling in striatonigral/direct pathway neurons, likely by activating (i) α4β2* nAChRs at dopaminergic terminals and (ii) α7 nAChRs at glutamatergic terminals, which, by stimulating the release of glutamate, activated NMDA/AMPA receptors at dopaminergic terminals. The differential effects of low and high nicotine concentrations on D2‐ and D1‐dependent signaling pathways in striatal neurons may contribute to dose‐dependent actions of this drug of abuse.
Arachidonic acid‐induced carbon‐centered radicals and phospholipid peroxidation in cyclo‐oxygenase‐2‐transfected PC12 cells
Authors: Jiang Jianfei , Borisenko Grigory G. , Osipov Anatoly , Martin Ian , Chen Renwu , Shvedova Anna A. , Sorokin Andrey , Tyurina Yulia Y. , Potapovich Alla , Tyurin Vladimir A. , Graham Steven H. , Kagan Valerian E. 
Published: August 2004

AbstractCyclo‐oxygenase‐2 (COX‐2) is believed to induce neuronal oxidative stress via production of radicals. While oxygen radicals are not directly involved in COX‐2‐catalytic cycle, superoxide anion radicals have been repeatedly reported to play a critical role in COX‐2‐associated oxidative stress. To resolve the controversy, we characterized production of free radicals in PC12 cells in which COX‐2 expression was manipulated either genetically or by direct protein transfection and compared them with those generated by a recombinant COX‐2 in a cell‐free system. Using spin‐traps α‐(4‐pyridyl‐1‐oxide)‐N‐t‐butylnitrone, 5,5‐dimethyl‐1‐pyrroline‐N‐oxide and 4‐((9‐acridinecarbonyl) amino)‐2,2,6,6‐ tetramethylpiperidine‐1‐oxyl (Ac‐Tempo), we observed arachidonic acid (AA)‐dependent production of carbon‐centered radicals by heme‐reconstituted recombinant COX‐2. No oxygen radicals or thiyl radicals have been detected. COX‐2 also catalyzed AA‐dependent one‐electron co‐oxidation of ascorbate to ascorbate radicals. Next, we used two different approaches of COX‐2 expression in cells, PCXII cells which express isopropyl‐1‐thio‐β‐d‐galactopyranoside inducible COX‐2, and PC12 cells transfected with COX‐2 using a protein delivery reagent, Chariot. In both models, COX‐2‐dependent AA‐induced generation of carbon‐centered radicals was documented using spin‐traps and Ac‐Tempo. No oxygen radical formation was detected in COX‐2‐transfected cells by either spin‐traps or fluorogenic probe, dihydroethidium. In the presence of ascorbate, AA‐induced COX‐2‐dependent ascorbate radicals were detected. AA caused a significant and selective oxidation of one of the major phospholipids, phosphatidylserine (PS). PS was not a direct substrate for COX‐2 but was co‐oxidized in the presence of AA. The radical generation and PS oxidation were inhibited by COX‐2 inhibitors, niflumic acid, nimesulide, or NS‐398. Thus, COX‐2 generated carbon‐centered radicals but not oxygen radicals or thiyl radicals are responsible for oxidative stress in AA‐challenged PC12 cells overexpressing COX‐2.
S. aureus‐dependent microglial activation is selectively attenuated by the cyclopentenone prostaglandin 15‐deoxy‐Δ12,14‐ prostaglandin J2 (15d‐PGJ2)
Authors: Kielian Tammy , McMahon Meredith , Bearden Edward D. , Baldwin Aaron C. , Drew Paul D , Esen Nilufer 
Published: August 2004

AbstractMicroglial activation is a hallmark of brain abscess. The continual release of proinflammatory mediators by microglia following bacterial challenge may contribute, in part, to the destruction of surrounding normal tissue characteristic of brain abscess. Therefore, attenuating chronic microglial activation during the course of CNS bacterial infections may have therapeutic benefits. The purpose of this study was to evaluate the ability of the natural peroxisome proliferator‐activated receptor (PPAR)‐γ agonist 15‐deoxy‐Δ12,14‐ prostaglandin J2 (15d‐PGJ2) to modulate microglial activation in response to Staphylococcus aureus, one of the main etiologic agents of brain abscess in humans. 15d‐PGJ2 was a potent inhibitor of proinflammatory cytokine (IL‐1β, TNF‐α, IL‐12 p40) and CC chemokine (MIP‐1β, MCP‐1) production in primary microglia, but had no effect upon the expression of select CXC chemokines (MIP‐2, KC). 15d‐PGJ2 also selectively inhibited the S. aureus‐dependent increase in microglial TLR2, CD14, MHC class II, and CD40 expression, whereas it had no effect on the co‐stimulatory molecules CD80 and CD86. Microarray analysis revealed additional inflammatory mediators modulated by 15d‐PGJ2 in primary microglia following S. aureus exposure, the majority of which were chemokines. These results suggest that suppressing microglial activation through the use of 15d‐PGJ2 may lead to the sparing of damage to normal brain parenchyma that often results from brain abscess.
An anti‐CD11d integrin antibody reduces cyclooxygenase‐2 expression and protein and DNA oxidation after spinal cord injury in rats
Authors: Bao Feng , Chen Yuhua , Dekaban Gregory A. , Weaver Lynne C. 
Published: August 2004

AbstractOur studies have shown that treatment with a monoclonal antibody (mAb) against the CD11d subunit of the leukocyte integrin CD11d/CD18 after spinal cord injury (SCI) decreases intraspinal inflammation, myeloperoxidase activity, lipid peroxidation and protein nitration, improving neurological function in rats. Using severe clip compression SCI in the rat, immunohistochemistry and western blotting were employed to assess the effects of an anti‐CD11d mAb treatment on spinal cord cyclooxygenase‐2 (COX‐2) expression, formation of 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG, a marker of RNA and DNA oxidation) and protein carbonylation (a marker of protein oxidation). We also assessed treatment effects on the expression of apurinic/apyrimidinic endonuclease (redox effector factor‐1, APE/Ref‐1), a multifunctional enzyme involved in the base excision repair of apurinic/apyrimidinic sites in DNA. The expression of COX‐2 and formation of 8‐OHdG and protein carbonyl groups were increased after SCI while APE/Ref‐1 expression was decreased. Anti‐CD11d mAb treatment clearly attenuated COX‐2 expression and 8‐OHdG and protein carbonyl formation and rescued APE/Ref‐1 expression after SCI. This study suggests that anti‐CD11d mAb treatment significantly reduces intraspinal free radical formation after SCI, thereby reducing protein and DNA oxidative damage. These effects likely underlie tissue preservation and improved neurological function resulting from the mAb treatment.
Apolipoprotein E modulates γ‐secretase cleavage of the amyloid precursor protein
Authors: Irizarry Michael C. , Deng Amy , Lleo Alberto , Berezovska Oksana , Von Arnim Christine A. F. , Martin‐Rehrmann Matthew , Manelli Arlene , LaDu Mary Jo , Hyman Bradley T. , Rebeck G. William 
Published: August 2004

AbstractPolymorphisms in the apolipoprotein E (APOE) gene affect the risk of Alzheimer disease and the amount of amyloid β‐protein (Aβ) deposited in the brain. The apoE protein reduces Aβ levels in conditioned media from cells in culture, possibly through Aβ clearance mechanisms. To explore this effect, we treated multiple neural and non‐neural cell lines for 24 h with apoE at concentrations similar to those found in the cerebrospinal fluid (1–5 µg/mL). The apoE treatment reduced Aβ40 by 60–80% and Aβ42 to a lesser extent (20–30%) in the conditioned media. Surprisingly, apoE treatment resulted in an accumulation of amyloid precursor protein (APP)‐C‐terminal fragments in cell extracts and a marked reduction of APP intracellular domain‐mediated signaling, consistent with diminished γ‐secretase processing of APP. All three isoforms of apoE, E2, E3 and E4, had similar effects on Aβ and APP‐C‐terminal fragments, and the effects were independent of the low‐density lipoprotein receptor family. Apolipoprotein E had minimal effects on Notch cleavage and signaling in cell‐based assays. These data suggest that apoE reduces γ‐secretase cleavage of APP, lowering secreted Aβ levels, with stronger effects on Aβ40. The apoE modulation of Aβ production and APP signaling is a potential mechanism affecting Alzheimer disease risk.
Epitope scanning reveals gain and loss of strain specific antibody binding epitopes associated with the conversion of normal cellular prion to scrapie prion
Authors: Pan Tao , Li Ruliang , Kang Shin‐Cheng , Wong Boon‐Seng , Wisniewski Thomas , Sy Man‐Sun 
Published: August 2004

AbstractWe used anti‐prion (PrP) monoclonal antibodies (Mabs) in different combinations to scan changes in the availability of antibody binding epitopes – using an epitope scanning assay – in brain homogenates from normal mice, and from mice infected with either ME7 or 139 A strains of infectious scrapie prion (PrPSc). In ME7‐infected brains, the epitope detected by the Mab pair 8B4/8H4 is reduced, while the epitope detected by the Mab pair 8F9/11G5 is increased. Mab 8F9/11G5 detect a conformational epitope on PrPScbecause the rise in Mab 8F9/11G5 binding is sensitive to a denaturing agent but resistant to proteinase K (PK). While the increase in Mab 8F9/11G5 binding correlates with the presence of PK‐resistant PrP and clinical signs of infection, the reduction in Mab 8B4/8H4 binding is detected earlier. Fractionation of the ME7‐infected brain homogenate in sucrose gradient revealed that the PrPScspecies detected by the epitope scanning assay are heterogeneous in size, with a molecular mass of ≈ ≥ 2000‐kDa. We also investigated whether these findings were applicable to two other strains of PrPSc, namely 87 V and 22 L. We found that the decrease in Mab 8B4/8H4 binding detected in ME7‐infected brains was also detected in 87 V‐infected brains but not in 22 L‐infected brains. In contrast, the increase in Mab 8F9/11G5 binding detected in ME7‐ and 139 A‐infected brains was also detected in 22 L‐infected brains but not in 87 V‐infected brains. Therefore, each prion strain has its unique conformation, and we can monitor the conversion of normal cellular prion (PrPC) to PrPScbased on the changes in the antibody binding patterns. The epitope can be decreased or increased, linear or conformational, detected late or early during infection, in a strain specific manner.
Excitatory amino acid induced oligodendrocyte cell death in vitro: receptor‐dependent and ‐independent mechanisms
Authors: Rosin Claudia , Bates Timothy E. , Skaper Stephen D. 
Published: August 2004

AbstractOligodendroglia play an important role in axonal conduction in the CNS and are sensitive to oxidative toxicity induced by glutamate in the absence of ionotropic glutamate receptors. In this study, oligodendrocyte signalling cascades were examined, in response to glutamate‐induced oxidative injury and to excitotoxicity. Rat cortical oligodendrocytes, differentiated in culture, were highly vulnerable to glutamate‐induced cell death. Competitive inhibition of cystine uptake and increased oxidative stress appeared responsible for this death, and caused an accumulation of intracellular peroxides as well as chromatin fragmentation and condensation. Glutamate receptor subtype agonists (quisqualate, ibotenate) known to inhibit cystine uptake were cytotoxic, but not NMDA itself; moreover, glutamate receptor antagonists were not protective. Oligodendrocytes were also vulnerable to overactivation of glutamate receptors, as kainic acid and AMPA proved to be toxic. AMPA toxicity required the presence of cyclothiazide, suggesting rapid desensitization of AMPA receptors. Glutamate‐induced oxidative stress and kainate/AMPA receptor stimulation activated the mitogen‐activated protein kinase (MAP kinase) pathway, as well as the transcription factor ELK. However, MAP kinase kinase inhibitors only protected against injury from glutamate‐induced oxidative stress. Oligodendrocytes were sensitive to oxygen–glucose deprivation injury as well, in a MAP kinase dependent fashion. Glutamate toxicity may conceivably be operative in neuropathological conditions that disrupt neuronal/oligodendrocyte interactions in axons, e.g. multiple sclerosis and ischaemia‐reperfusion injury.
DASB –in vitro binding characteristics on human recombinant monoamine transporters with regard to its potential as positron emission tomography (PET) tracer
Authors: Hummerich René , Reischl Gerald , Ehrlichmann Walter , Machulla Hans‐Jürgen , Heinz Andreas , Schloss Patrick 
Published: August 2004

AbstractThe efficiency of serotonergic signal transduction is controlled by the density of serotonegic synapses and by the activity of the serotonin transporter (SERT), which selectively clears the synaptic cleft of the neurotransmitter. SERT is located in axons, where it is concentrated in varicosities and terminal boutons and thus is an exquisite marker for serotonergic synapses. This finding has been taken advantage of for neuroimaging serotonergic synaptic contact sites. Previous positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies were often carried out using radioligands that bind with high affinity to SERTs in the brainstem but also exhibit high affinity for dopamine and norepinephrine transporters and therefore did not allow quantification of serotonergic innervations in brain regions also containing dopaminergic or noradrenergic terminals. In order to visualize SERT availability more selectively, in recent years new tracers have been developed, one of which is [11C]DASB (N,N‐dimethyl‐2‐2‐amino‐4‐cyanophenylthiobenzylamine). Here, we have performed a detailed pharmacological characterization of unlabelled as well as radioactive DASB on recombinant human monoamine transporter proteins. Our results show that DASB selectively binds to SERT with high affinity (KD = 3.5 nm) to a site distinct from the serotonin (5‐HT) recognition/translocation site. 5‐HT inhibits DASB binding to SERT with more than one order of magnitude lower affinity than that of DASB binding (IC50 = 82.4 nm). These findings suggest DASB to be a highly selective PET tracer to visualize the density of serotonergic synapses in human brain.
The C‐terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: involvement of phosphatidylinositol 3‐kinase and mitogen‐activated protein kinase pathways
Authors: Chaïb‐Oukadour Imane , Gil Carles , Aguilera José 
Published: August 2004

AbstractWhen cultured cerebellar granule neurones are transferred from a medium containing high extracellular potassium concentration ([K+]e) (25 mm) to one with lower [K+]e (5 mm), caspase‐3 activity is induced and cells die apoptotically. In contrast, if cells in non‐depolarizing conditions are treated with brain‐derived neurotrophic factor (BDNF), caspase‐3 activity, chromatin condensation and cell death are markedly diminished. In this study, we show that the C‐terminal domain of the tetanus toxin heavy‐chain (Hc‐TeTx) is able to produce the same neuroprotective effect, as assessed by reduction of tetrazolium salts and by chromatin condensation. Hc‐TeTx‐conferred neuroprotection appears to depend on phosphatidylinositol 3‐kinase (PI3K) and mitogen‐activated protein kinase kinase, as is demonstrated by the selective inhibitors Wortmannin and PD98059, respectively. Hc‐TeTx also induces phosphorylation of the tyrosine kinase BDNF receptor, activation of p21Ras in its GTP‐bound form, and phosphorylation of the cascade including extracellular‐signal‐regulated kinases‐1/2 (ERK‐1/2), p90 ribosomal S6 kinase (p90rsk) and CREB (cAMP‐response‐element‐binding protein). On the other hand, activation of the Akt pathway is also detected, as well as inhibition of the active form of caspase‐3. These results point to an implication of both PI3K‐ and ERK‐dependent pathways in the promotion of cerebellar granule cell survival by Hc‐TeTx.
Zinc inhibits glutamate release via activation of pre‐synaptic KATP channels and reduces ischaemic damage in rat hippocampus
Authors: Bancila Victor , Nikonenko Irina , Dunant Yves , Bloc Alain 
Published: August 2004

AbstractZinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4‐aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP‐sensitive potassium channels (KATP), since they were mimicked by the KATP opener diazoxide and antagonized by the KATP blocker tolbutamide. Using recombinant channels expressed in COS‐7 cells, we confirmed that micromolar zinc did activate KATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxic‐hypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through KATP, as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre‐synaptic KATP channels, zinc protects neurones from hyper‐excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.
Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosispatients
Authors: Ferri Alberto , Nencini Monica , Battistini Stefania , Giannini Fabio , Siciliano Gabriele , Casali Carlo , Damiano Maria G. , Ceroni Mauro , Chiò Adriano , Rotilio Giuseppe , Carrì Maria Teresa 
Published: August 2004

AbstractCalcineurin (CaN) is a Ser/Thr protein phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion that calcineurin is oxidatively inhibited by mutant Cu, Zn superoxide dismutase (SOD1) typical of familial ALS patients in vitro and in transgenic mice. We report that calcineurin activity is markedly inhibited in lymphocytes from 37 sporadic, eight familial ALS patients and an asymptomatic subject carrying an SOD1 mutation as compared to 28 healthy controls. Two other healthy subjects, heterozygous for the D90A mutation from a recessive pedigree, have normal calcineurin activity. Immunoreactive CaN protein, age, sex and riluzole treatment are not related to calcineurin activity in samples from patients. However, we have observed a marked increase in total protein oxidation in extracts from ALS lymphocytes, as compared to extracts from control subjects. These data confirm that modification of calcineurin activity and possibly of calcineurin‐mediated pathways of signal transduction (including modulation of apoptotic neuronal death) may contribute to the pathogenesis of ALS.
Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant‐like effects
Authors: Shirayama Yukihiko , Ishida Hisahito , Iwata Masaaki , Hazama Gen‐i , Kawahara Ryuzou , Duman Ronald S. 
Published: August 2004

AbstractRats exposed to learned helplessness (LH), an animal model of depression, showed a recovery following an intracerebroventricular injection of nor‐binaltorphimine dihydrochloride (norBNI; a κ‐opioid antagonist). To investigate the potential role of dynorphin A and dynorphin B, we examined the effects of different stress/depression models on dynorphin A and dynorphin B immunoreactivity in hippocampus and nucleus accumbens (NAc). Immobilization stress (3 h) caused an increase in levels of dynorphin A and dynorphin B immunoreactivity in the hippocampus and the NAc. Forced swim stress also temporally increased dynorphin A levels in the hippocampus. Furthermore, exposure to LH produced a similar increase in dynorphin A and dynorphin B in the hippocampus and NAc. Infusions of norBNI into the dentate gyrus or CA3 regions of hippocampus and into the shell or core regions of NAc produced antidepressant‐like effects in the LH paradigm. The degrees of norBNI's effects were stronger in the CA3 region and NAc shell and less effective in the dentate gyrus of hippocampus and NAc core. These results indicate that both dynorphin A and dynorphin B contribute to the effects of stress, and suggest that blockade of κ‐opioid receptors may have therapeutic potential for the treatment of depression.