bluuebunny/crossref_metadata_2025_split huggingface dataset:
8‐[2‐(2‐pentyl‐cyclopropylmethyl)‐cyclopropyl]‐octanoic acid stimulates GABA release from interneurons projecting to CA1 pyramidal neurons in the rat hippocampus via pre‐synaptic α7 acetylcholine receptors
Authors: Kanno Takeshi , Yaguchi Takahiro , Yamamoto Satoshi , Yamamoto Hideyuki , Fujikawa Hirokazu , Nagata Tetsu , Tanaka Akito , Nishizaki Tomoyuki 
Published: August 2005

AbstractNicotinic acetylcholine (ACh) receptors, such as α7, α3β4 and α4β2 receptors in the hippocampus, are suggested to modulate neurotransmitter release. 8‐[2‐(2‐Pentyl‐cyclopropylmethyl)‐cyclopropyl]‐octanoic acid (DCP‐LA) (100 nm), a linoleic acid derivative, potentiated responses of α7, α3β4 and α4β2 ACh receptors expressed in Xenopus oocytes that are blocked by 3‐(1‐[dimethylaminopropyl] indol‐3‐yl)‐4‐[indol‐3‐yl] maleimide (GF109203X), a selective inhibitor of protein kinase C (PKC), except for α3β4 ACh receptors. DCP‐LA enhanced the nicotine‐triggered release of GABA from rat hippocampal slices in the presence of tetrodotoxin in a bell‐shaped dose‐dependent manner at concentrations ranging from 10 nm to 10 µm, although DCP‐LA by itself had no effect on GABA release. The DCP‐LA action was inhibited by GF109203X or α‐bungarotoxin, an inhibitor of α7 ACh receptors, but not by mecamylamine or dihydro‐β‐erithroidine, an inhibitor of α3β4 and α4β2 ACh receptors. A similar effect on GABA release was obtained with 12‐O‐tetradecanoylphorbol 13‐acetate, a PKC activator. DCP‐LA (100 nm) also enhanced GABA release triggered by choline, an agonist of α7 ACh receptors, but not 3‐[2(s)‐azetidinylmethoxy] pyridine, an agonist of α4β2 ACh receptors. In addition, DCP‐LA (100 nm) increased the rate of nicotine‐triggered GABAA receptor‐mediated miniature inhibitory post‐synaptic currents, monitored from CA1 pyramidal neurons of rat hippocampal slices, and the effect was also inhibited by GF109203X or α‐bungarotoxin but not by mecamylamine. Thus, the results of the present study indicate that DCP‐LA stimulates GABA release by enhancing activity of pre‐synaptic α7 ACh receptors present on the GABAergic terminals of interneurons that transmit to CA1 pyramidal neurons via a PKC pathway.
Transcription factor specificity protein 1 (Sp1) is the main regulator of nerve growth factor‐induced sphingosine kinase 1 gene expression of the rat pheochromocytoma cell line, PC12
Authors: Sobue S. , Hagiwara K. , Banno Y. , Tamiya‐Koizumi K. , Suzuki M. , Takagi A. , Kojima T. , Asano H. , Nozawa Y. , Murate T. 
Published: August 2005

AbstractSphingosine kinase (SPHK) is known to exert an anti‐apoptic role in various cells and cell lines. We previously reported that human brain is rich in SPHK1 (Murate et al. 2001). After showing a high expression of SPHK1 in rat brain, we examined the gene expression mechanism using nerve growth factor (NGF) ‐stimulated rat PC12 cells. With RT–PCR, we found that both rat brain and PC12 utilized exon 1d mostly out of eight untranslated first exons. NGF induced an increase in SPHK enzyme activity and protein about double those in PC12 cells, and NGF‐induced SPHK1 mRNA was three times higher than in the control. The minimal 5′ promoter was determined, and TrkA specific inhibitor K252a inhibited the NGF‐induced promoter activity of SPHK1. The truncation or mutation of putative transcription factor‐binding motifs revealed that one specificity protein 1 (Sp1) binding motif of the 5′ region of exon 1d is prerequisite. Electrophoresis mobility shift assay confirmed the promoter analysis, indicating increased Sp1 protein binding to this motif after NGF treatment. Chromatin immunoprecipitation assay also showed the binding of Sp1 and the promoter region in vivo. These results suggest the signal transduction pathway from NGF receptor TrkA to transcription factor Sp1 protein binding to the promoter Sp1‐like motif in NGF‐induced rat SPHK1 gene expression.
Genetically rescued tetrahydrobiopterin‐depleted mice survive with hyperphenylalaninemia and region‐specific monoaminergic abnormalities
Authors: Sumi‐Ichinose Chiho , Urano Fumi , Shimomura Atsushi , Sato Takashi , Ikemoto Kazuhisa , Shiraishi Hiroaki , Senda Takao , Ichinose Hiroshi , Nomura Takahide 
Published: August 2005

AbstractOne of the possibly mutated genes in DOPA‐responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate‐limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6‐pyruvoyltetrahydropterin synthase (PTS) gene‐disrupted (Pts–/–) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts–/– mice by transgenic introduction of human PTS cDNA under the control of the dopamine β‐hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4‐insufficiency. The DPS‐rescued (Pts–/–, DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH‐immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4‐insufficiency. Biochemical and pathological changes in DPS‐rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.
Differential effects of human neuromelanin and synthetic dopamine melanin on neuronal and glial cells
Authors: Li Jie , Scheller Carsten , Koutsilieri Eleni , Griffiths Francine , Beart Philip M. , Mercer Linda D. , Halliday Glenda , Kettle Emma , Rowe Dominic , Riederer Peter , Gerlach Manfred , Rodriguez Michael , Double Kay L. 
Published: August 2005

AbstractWe investigated the effects of neuromelanin (NM) isolated from the human substantia nigra and synthetic dopamine melanin (DAM) on neuronal and glial cell lines and on primary rat mesencephalic cultures. Lactate dehydrogenase (LDH) activity and lipid peroxidation were significantly increased in SK‐N‐SH cells by DAM but not by NM. In contrast, iron‐saturated NM significantly increased LDH activity in SK‐N‐SH cells, compared with 100 mg/mL ETDA‐treated NM containing a low concentration of bound iron. DAM, but not NM, stimulated hydroxyl radical production and increased SK‐N‐SH cell death via apoptotic‐like mechanisms. Neither DAM nor NM induced any changes in the glial cell line U373. 3H‐Dopamine uptake in primary rat mesencephalic cultures was significantly reduced in DAM‐ compared with NM‐treated cultures, accompanied by increased cell death via an apoptosis‐like mechanism. Interestingly, Fenton‐induced cell death was significantly decreased in cultures treated with both Fenton reagent and NM, an effect not seen in cultures treated with Fenton reagent plus DAM. These data are suggestive of a protective role for neuromelanin under conditions of high oxidative load. Our findings provide new evidence for a physiological role for neuromelanin in vivo and highlights the caution with which data based upon model systems should be interpreted.
Globular amyloid β‐peptide1−42 oligomer − a homogenous and stable neuropathological protein in Alzheimer's disease
Authors: Barghorn Stefan , Nimmrich Volker , Striebinger Andreas , Krantz Carsten , Keller Patrick , Janson Bodo , Bahr Michael , Schmidt Martin , Bitner Robert S. , Harlan John , Barlow Eve , Ebert Ulrich , Hillen Heinz 
Published: August 2005

AbstractAmyloid β‐peptide (Aβ)1−42 oligomers have recently been discussed as intermediate toxic species in Alzheimer's disease (AD) pathology. Here we describe a new and highly stable Aβ1−42 oligomer species which can easily be prepared in vitro and is present in the brains of patients with AD and Aβ1−42‐overproducing transgenic mice. Physicochemical characterization reveals a pure, highly water‐soluble globular 60‐kDa oligomer which we named ‘Aβ1−42 globulomer’. Our data indicate that Aβ1−42 globulomer is a persistent structural entity formed independently of the fibrillar aggregation pathway. It is a potent antigen in mice and rabbits eliciting generation of Aβ1−42 globulomer‐specific antibodies that do not cross‐react with amyloid precursor protein, Aβ1−40 and Aβ1−42 monomers and Aβ fibrils. Aβ1−42 globulomer binds specifically to dendritic processes of neurons but not glia in hippocampal cell cultures and completely blocks long‐term potentiation in rat hippocampal slices. Our data suggest that Aβ1−42 globulomer represents a basic pathogenic structural principle also present to a minor extent in previously described oligomer preparations and that its formation is an early pathological event in AD. Selective neutralization of the Aβ globulomer structure epitope is expected to have a high potential for treatment of AD.
P2Y2 nucleotide receptor interaction with αV integrin mediates astrocyte migration
Authors: Wang Min , Kong Qiongman , Gonzalez Fernando A. , Sun Grace , Erb Laurie , Seye Cheikh , Weisman Gary A. 
Published: August 2005

AbstractAstrocytes become activated in response to brain injury, as characterized by increased expression of glial fibrillary acidic protein (GFAP) and increased rates of cell migration and proliferation. Damage to brain cells causes the release of cytoplasmic nucleotides, such as ATP and uridine 5′‐triphosphate (UTP), ligands for P2 nucleotide receptors. Results in this study with primary rat astrocytes indicate that activation of a G protein‐coupled P2Y2 receptor for ATP and UTP increases GFAP expression and both chemotactic and chemokinetic cell migration. UTP‐induced astrocyte migration was inhibited by silencing of P2Y2 nucleotide receptor (P2Y2R) expression with siRNA of P2Y2R (P2Y2R siRNA). UTP also increased the expression in astrocytes of αVβ3/5 integrins that are known to interact directly with the P2Y2R to modulate its function. Anti‐αV integrin antibodies prevented UTP‐stimulated astrocyte migration, suggesting that P2Y2R/αV interactions mediate the activation of astrocytes by UTP. P2Y2R‐mediated astrocyte migration required the activation of the phosphatidylinositol‐3‐kinase (PI3‐K)/protein kinase B (Akt) and the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MEK/ERK) signaling pathways, responses that also were inhibited by anti‐αV integrin antibody. These results suggest that P2Y2Rs and their associated signaling pathways may be important factors regulating astrogliosis in brain disorders.
Proliferation of microglial cells induced by 1‐methyl‐4‐phenylpyridinium in mesencephalic cultures results from an astrocyte‐dependent mechanism: role of granulocyte macrophage colony‐stimulating factor
Authors: Henze Carmen , Hartmann Andreas , Lescot Thomas , Hirsch Etienne C. , Michel Patrick P. 
Published: August 2005

AbstractThere is evidence that an inflammatory microglial reaction participates in the pathophysiology of dopaminergic neuronal death in Parkinson's disease and in animal models of the disease. However, this phenomenon remains incompletely characterized. Using an in vitro model of neuronal/glial mesencephalic cultures, we show that the dopaminergic neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP+) stimulates the proliferation of microglial cells at concentrations that selectively reduce the survival of DA neurones. The mitogenic action of MPP+ was not the mere consequence of neuronal cell demise as the toxin produced the same effect in a model system of neuronal/glial cortical cultures, where target DA neurones are absent. Consistent with this observation, the proliferative effect of MPP+ was also detectable in neurone‐free microglial/astroglial cultures. It disappeared, however, when MPP+ was added to pure microglial cell cultures suggesting that astrocytes played a key role in the mitogenic mechanism. Accordingly, the proliferation of microglial cells in response to MPP+ treatment was mimicked by granulocyte macrophage colony‐stimulating factor (GM‐CSF), a proinflammatory cytokine produced by astrocytes and was blocked by a neutralizing antibody to GM‐CSF. Thus, we conclude that the microglial reaction observed following MPP+ exposure depends on astrocytic factors, e.g. GM‐CSF, a finding that may have therapeutic implications.
Mitochondrial medicine: neuroprotection and life extension by the new amphiphilic nitrone LPBNAH1 acting as a highly potent antioxidant agent
Authors: Poeggeler Burkhard , Durand Grégory , Polidori Ange , Pappolla Miguel A. , Vega‐Naredo Ignacio , Coto‐Montes Ana , Böker Jutta , Hardeland Rüdiger , Pucci Bernard 
Published: August 2005

AbstractThe search for effective treatments that prevent oxidative stress associated with premature ageing and neurodegenerative diseases is an important area of neurochemical research. As age‐ and disease‐related oxidative stress is frequently associated with mitochondrial dysfunction, amphiphilic antioxidant agents of high stability and selectivity that target these organelles can provide on‐site protection. Such an amphiphilic nitrone protected human neuroblastoma cells at low micromolar concentrations against oxidative damage and death induced by exposure to the β‐amyloid peptide, hydrogen peroxide and 3‐hydroxykynurenine. Daily administration of the antioxidant at a concentration of only 5 μm significantly increased the lifespan of the individually cultured rotifer Philodina acuticornis odiosa Milne. This compound is unique in its exceptional anti‐ageing efficacy, being one order of magnitude more potent than any other compound previously tested on rotifers. The nitrone protected these aquatic animals against the lethal toxicity of hydrogen peroxide and doxorubicin and greatly enhanced their survival when co‐administered with these oxidotoxins. These findings indicate that amphiphilic antioxidants have a great potential as neuroprotective agents in preventing the death of cells and organisms exposed to enhanced oxidative stress and damage.
CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism
Authors: Silva Robert M. , Ries Vincent , Oo Tinmarla Frances , Yarygina Olga , Jackson‐Lewis Vernice , Ryu Elizabeth J. , Lu Phoebe D. , Marciniak Stefan M. , Ron David , Przedborski Serge , Kholodilov Nikolai , Greene Lloyd A. , Burke Robert E. 
Published: August 2005

AbstractThere is increasing evidence that neuron death in neurodegenerative diseases, such as Parkinson's disease, is due to the activation of programmed cell death. However, the upstream mediators of cell death remain largely unknown. One approach to the identification of upstream mediators is to perform gene expression analysis in disease models. Such analyses, performed in tissue culture models induced by neurotoxins, have identified up‐regulation of CHOP/GADD153, a transcription factor implicated in apoptosis due to endoplasmic reticulum stress or oxidative injury. To evaluate the disease‐related significance of these findings, we have examined the expression of CHOP/GADD153 in neurotoxin models of parkinsonism in living animals. Nuclear expression of CHOP protein is observed in developmental and adult models of dopamine neuron death induced by intrastriatal injection of 6‐hydroxydopamine (6OHDA) and in models induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). CHOP is a mediator of neuron death in the adult 60HDA model because a null mutation results in a reduction in apoptosis. In the chronic MPTP model, however, while CHOP is robustly expressed, the null mutation does not protect from the loss of neurons. We conclude that the role of CHOP depends on the nature of the toxic stimulus. For 6OHDA, an oxidative metabolite of dopamine, it is a mediator of apoptotic death.
Autocrine activation of EGF receptor promotes oscillation of glutamate‐induced calcium increase in astrocytes cultured in rat cerebral cortex
Authors: Morita Mitsuhiro , Kozuka Nagisa , Itofusa Rurika , Yukawa Masashi , Kudo Yosihisa 
Published: August 2005

AbstractWe previously reported that astrocytes cultured for more than 2 days in a defined medium containing epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) showed calcium oscillation in response to glutamate, whereas the response pattern was transient in the absence of the exogenous growth factors. In the present study, we found that astrocytes showed glutamate‐induced calcium oscillation, even in growth factor‐free medium, if the cells had been cultured for more than 5 days. The calcium oscillation promoted by the prolonged culture period was suppressed by an inhibitor of EGF receptor tyrosine kinase, but not by a neutralizing antibody to bFGF, indicating that the accumulation of an autocrine factor that activates the EGF receptor leads to calcium oscillation. Astrocytes in our culture system expressed EGF, transforming growth factor α (TGFα), bFGF and acidic fibroblast growth factor (aFGF). Exogenous aFGF, which induced astrocyte immediate early gene expression to the same extent as EGF or bFGF, did not affect calcium oscillation. Exogenous EGF and bFGF promoted astrocyte hypertrophic morphology and proliferation, as well as calcium oscillation. In contrast, these properties did not accompany calcium oscillation induced by the prolonged culture period. These results suggest that astrocytes possess the ability to promote their own calcium oscillation, which is independent of hypertrophic changes to reactive astrocytes.
Divergent modulation of iron regulatory proteins and ferritin biosynthesis by hypoxia/reoxygenation in neurones and glial cells
Authors: Irace Carlo , Scorziello Antonella , Maffettone Carmen , Pignataro Giuseppe , Matrone Carmela , Adornetto Annagrazia , Santamaria Rita , Lucio Annunziato  , Colonna Alfredo 
Published: August 2005

AbstractFerritin, the main iron storage protein, exerts a cytoprotective effect against the iron‐catalyzed production of reactive oxygen species, but its role in brain injury caused by hypoxia/reoxygenation is unclear. Ferritin expression is regulated mainly at post‐transcriptional level by iron regulatory proteins (IRP1 and IRP2) that bind specific RNA sequences (IREs) in the 5′untranslated region of ferritin mRNA. Here, we show that hypoxia decreases IRP1 binding activity in glial cells and enhances it in cortical neurons. These effects were reversed by reoxygenation in both cell types. In glial cells there was an early increase of ferritin synthesis during hypoxia and reoxygenation. Conversely, in cortical neurons, ferritin synthesis increased during the late phase of reoxygenation. Steady‐state analysis of ferritin mRNA levels suggested that ferritin synthesis is regulated mainly post‐transcriptionally by IRPs in glioma cells, both transcriptionally and post‐transcriptionally in type‐1 astrocytes, and mainly at transcriptional level in an IRP‐independent way in neurons. The different regulation of ferritin expression may account for the different vulnerability of neurons and glial cells to the injury elicited by oxygen and glucose deprivation (OGD)/reoxygenation. The greater vulnerability of cortical neurons to hypoxia‐reoxygenation was strongly attenuated by the exogenous administration of ferritin during OGD/reoxygenation, suggesting the possible cytoprotective role exerted by this iron‐segregating protein.
Parent‐Identified Barriers to Pediatric Health Care: A Process‐Oriented Model
Authors: Sobo Elisa J. , Seid Michael , Gelhard Leticia Reyes 
Published: September 2005

Objective. To further understand barriers to care as experienced by health care consumers, and to demonstrate the importance of conjoining qualitative and quantitative health services research.Data Sources. Transcripts from focus groups conducted in San Diego with English‐ and Spanish‐speaking parents of children with special health care needs.Study Design. Participants were asked about the barriers to care they had experienced or perceived, and their strategies for overcoming these barriers. Using elementary anthropological discourse analysis techniques, a process‐based conceptual model of the parent experience was devised.Principal Findings. The analysis revealed a parent‐motivated model of barriers to care that enriched our understanding of quantitative findings regarding the population from which the focus group sample was drawn. Parent‐identified barriers were grouped into the following six temporally and spatially sequenced categories: necessary skills and prerequisites for gaining access to the system; realizing access once it is gained; front office experiences; interactions with physicians; system arbitrariness and fragmentation; outcomes that affect future interaction with the system. Key to the successful navigation of the system was parents' functional biomedical acculturation; this construct likens the biomedical health services system to a cultural system within which all parents/patients must learn to function competently.Conclusions. Qualitative analysis of focus group data enabled a deeper understanding of barriers to care—one that went beyond the traditional association of marker variables with poor outcomes (“what”) to reveal an understanding of the processes by which parents experience the health care system (“how,”“why”) and by which disparities may arise. Development of such process‐oriented models furthers the provision of patient‐centered care and the creation of interventions, programs, and curricula to enhance such care. Qualitative discourse analysis, for example using this project's widely applicable protocol for generating experientially based models, can enhance our knowledge of the parent/patient experience and aid in the development of more powerful conceptualizations of key health care constructs.
Diffusion Tensor Imaging in Late Posttraumatic Epilepsy
Authors: Gupta Rakesh K. , Saksena Sona , Agarwal Atul , Hasan Khader M. , Husain Mazhar , Gupta Vikas , Narayana Ponnada A. 
Published: September 2005

Summary:  Purpose: The main objective of this study was to use diffusion tensor imaging (DTI) to search and quantify the extent of abnormality beyond the obvious lesions seen on the T2 and fluid‐attenuation inversion recovery (FLAIR) magnetic resonance images in patients with chronic traumatic brain injury (TBI) with and without epilepsy. Methods: DTI was performed on 23 chronic TBI patients (with late posttraumatic epilepsy, n = 14; without epilepsy, n = 9) and 11 age‐matched controls. The ratios of fractional anisotropy (FA) and mean diffusivity (MD) between the regions of interest beyond the T2/FLAIR‐visualized abnormality and the corresponding contralateral normal‐appearing region were calculated. FA and MD ratios were compared for relative changes in these parameters among the TBI subjects with and without epilepsy and controls. Tissue volumes exhibiting abnormalities on DTI also were measured in these patients. Results: The mean regional FA ratio was significantly lower, whereas the mean regional MD value was higher in patients with TBI compared with controls. The mean regional FA ratio was significantly lower in TBI patients with epilepsy (0.57 ± 0.059) than in those without epilepsy (0.68 ± 0.039). Although the regional MD ratio was higher in TBI patients with epilepsy (1.15 ± 0.140) relative to those without epilepsy (1.09 ± 0.141), the difference did not reach statistical significance. The tissue volume with low FA value also was found to be higher in TBI patients with epilepsy than without. Conclusions: Severity of injury as predicted by the DTI‐derived increased volume of microstructure damage is associated with delayed posttraumatic epilepsy in TBI patients. These findings could be valuable in predicting epileptogenesis in patients with chronic TBI.