bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular mechanisms of glutamate neurotoxicity in mixed cultures of NT2‐derived neurons and astrocytes: Protective effects of coenzyme Q10
Authors: Sandhu Jagdeep K. , Pandey Siyaram , Ribecco‐Lutkiewicz Maria , Monette Robert , Borowy‐Borowski Henryk , Walker P. Roy , Sikorska Marianna 
Published: May 2003

AbstractAlthough glutamate excitotoxicity has long been implicated in neuronal cell death associated with a variety of neurological disorders, the molecular mechanisms underlying this process are not yet fully understood. In part, this is due to the lack of relevant experimental cell systems recapitulating the in vivo neuronal environment, mainly neuronal–glial interactions. To explore these mechanisms, we have analyzed the cytotoxic effects of glutamate on mixed cultures of NT2/N neurons and NT2/A astrocytes derived from human NT2/D1 cells. In these cultures, the neurons were resistant to glutamate alone (up to 2 mM for 24–48 hr), but they responded to a simultaneous exposure to 0.5 mM glutamate and 6 hr of hypoxia. Neuronal cell death occurred during subsequent periods of reoxygenation (>30% within 24 hr). This was associated with a marked decrease of intracellular ATP, a significant increase in reactive oxygen species (ROS) and downregulation of glutamate uptake by astrocytes. Thus, under energy failure and high levels of ROS production, only the neurons from these mixed cultures succumbed to glutamate neurotoxicity; the astrocytic cells remained unaffected by the treatment. Taken together, our data suggested that glutamate excitotoxicity might be due to the energy failure and oxidative stress affecting the properties of the NMDA glutamate receptors and causing impairment of glutamate transporters. Cells pretreated for 72 hr with 10 μg/ml of coenzyme Q10 (functions both as a ROS scavenger and co‐factor of mitochondrial electron transport), were protected, suggesting a useful role for coenzyme Q10 in treatments of neurological diseases associated with glutamate excitotoxicity. A model of the complex interactions between neurons and astrocytes in regulating glutamate metabolism is presented. © 2003 Government of Canada. Exclusive worldwide publication rights in the article have been transferred to Wiley‐Liss, Inc.
Testosterone up‐regulates aquaporin‐4 expression in cultured astrocytes
Authors: Gu Feng , Hata Ryuji , Toku Kazuko , Yang Lihua , Ma Yong‐Jie , Maeda Nobuji , Sakanaka Masahiro , Tanaka Junya 
Published: May 2003

AbstractAquaporin‐4 (AQP4) is located on astrocyte endfeet that face blood vessels in the brain and in the pia. It is thought to play a crucial role in the development of brain edema. To confirm the notion that sex steroids and dexamethasone influence brain edema through AQP4 regulation, we investigated the effects of 17β‐estradiol, testosterone, and dexamethasone on the expression of AQP4 in cultured astrocytes. Testosterone significantly up‐regulated AQP4 at the level of both protein and mRNA. At a concentration of 100 nM, testosterone significantly increased AQP4 protein levels and ameliorated the osmotic fragility of astrocytes from hypoosmotic stress, suggesting that the increased levels of AQP4 facilitated the testosterone function. Moreover, this effect was attenuated by the protein kinase C activator 12‐O‐tetradecanoylphorbol 13‐acetate, which can rapidly decrease AQP4 mRNA expression, indicating that the response was specific. These results indicate that AQP4 can alter the osmotic fragility of astrocytes and that testosterone can influence brain edema through AQP4 regulation, whereas 17β‐estradiol and dexamethasone cannot. © 2003 Wiley‐Liss, Inc.
Effects of peroxisome proliferator‐activated receptor γ ligands ciglitazone and 15‐deoxy‐Δ12,14‐prostaglandin J2 on rat cultured cerebellar granule neuronal viability
Authors: Smith Steven A. , Monteith Gregory R. , Holman Nicola A. , Robinson Jodie A. , May Fiona J. , Roberts‐Thomson Sarah J. 
Published: May 2003

AbstractPeroxisome proliferator‐activated receptor γ (PPARγ) has been the focus of studies assessing its potential neuroprotective role. These studies have shown either neuroprotection or neurotoxicity by PPARγ ligands. Comparison of these studies is complicated by the use of different PPARγ ligands, mechanisms of neurotoxicity induction, and neuronal cell type. In this study, we compared the effects of the synthetic PPARγ ligand ciglitazone with an endogenous PPARγ ligand, 15‐deoxy‐Δ12,14‐prostaglandin J2 (15‐deoxy PGJ2), on inherent neurotoxicity and neuroprotection using a reduction in extracellular KCl in rat cultured cerebellar granule neurons (CGN). We also assessed the effects of these ligands on c‐Jun protein expression, which is up‐regulated on induction of low‐KCl‐mediated neuronal apoptosis as well as being associated with PPAR in other cell types. We showed that PPARγ mRNA is expressed in CGN cultures and observed ciglitazone‐ and 15‐deoxy PGJ2‐mediated inherent neurotoxicity that was concentration and time dependent. c‐Jun was only modestly increased in the presence of ciglitazone but was markedly up‐regulated by 15‐deoxy PGJ2 after 12 hr. Treatment of CGN cultures with ciglitazone simultaneous with KCl withdrawal resulted in a modest, time‐dependent neuroprotection. Such neuroprotection after KCl withdrawal was not observed with 15‐deoxy PGJ2. Despite the absence of neuroprotection, 15‐deoxy PGJ2 markedly inhibited the early up‐regulation of c‐Jun during KCl withdrawal. These studies suggest that ciglitazone and 15‐deoxy PGJ2 have markedly different effects on inherent and low‐KCl‐induced toxicity and c‐Jun expression in CGN, indicating potential non‐PPARγ mechanisms. © 2003 Wiley‐Liss, Inc.
Transplantation of human adult astrocytes: Efficiency and safety requirements for an autologous gene therapy
Authors: Ridet Jean‐Luc , Sarkis Chamsy , Serguera Che , Zennou Véronique , Charneau Pierre , Mallet Jacques 
Published: May 2003

AbstractEx vivo gene therapy is emerging as a promising approach for the treatment of neurodegenerative diseases and central nervous system (CNS) trauma. We have shown previously that human adult astrocytes can be expanded in vitro and can express various therapeutic transgenes (Ridet et al. [1999] Hum. Gene Ther. 10:271–280; Serguera et al. [ 2001] Mol. Ther. 3:875–881). Here, we grafted normal and lentivirally‐modified human adult astrocytes into the striatum and spinal cord of nude mice to test whether they are suitable candidates for ex vivo CNS gene therapy. Transplanted cells survived for at least 2 months (longest time analyzed) and sustained transgene expression. Importantly, the absence of proliferating cell nuclear antigen (PCNA) staining, a hallmark of cell division, ascertains the safety of these cells. Thus, adult human astrocytes are a promising tool for human CNS repair; they may make autologous ex vivo gene transfer feasible, thereby avoiding the problems of immunological rejection and the side effects of immunosuppressors. © 2003 Wiley‐Liss, Inc.
Lymphocyte infiltration in the injured brain: Role of proinflammatory cytokines
Authors: Raivich Gennadij , Bohatschek Marion , Werner Alexander , Jones Leonard L. , Galiano Matthias , Kloss Christian U.A. , Zhu Xing‐Zu , Pfeffer Klaus , Liu Zhi Qiang 
Published: May 2003

AbstractStudies using mouse axotomised facial motoneuron model show a strong and highly selective entry of CD3+ lymphocytes into the affected nucleus, with a maximum at Day 14, which coincides with the peak of neuronal cell death, microglial phagocytosis, and increased synthesis of interleukin‐1 beta (IL1β), tumour necrosis factor‐alpha (TNFα) and interferon‐gamma (IFNγ). We explored the possible involvement of these cytokines during the main phase of lymphocyte recruitment into the axotomised facial motor nucleus 7–21 days after nerve cut using mice homozygously deficient for IL1 receptor type 1 (IL1R1−/−), TNF receptor type 1 (TNFR1−/−), type 2 (TNFR2−/−) and type 1 and 2 (TNFR1&2−/−), IFNγ receptor type 1 (IFNγR1−/−), and the appropriate controls for the genetic background. Transgenic deletion of IL1R1 led to a 54% decrease and that of TNFR2 to a 44% reduction in the number of CD3+ T‐cells in the axotomised facial motor nucleus, with a similar relative decrease at Day 7, 14, and 21. Deletion of TNFR1 or IFNγR1 had no significant effect. Deletion of both TNFR1 and 2 (TNFR1&2−/−) caused a somewhat stronger, 63% decrease than did TNFR2 deletion alone, but this could be due to an almost complete inhibition of neuronal cell death. No mutations seemed to inhibit aggregation of CD3+ T‐cells around glial nodules consisting of Ca‐ion binding adaptor protein‐1 (IBA1)+ phagocytotic microglia and neuronal debris. Altogether, the current data show the importance of IL1R1 and TNFR2 as the key players during the main phase of lymphocyte recruitment to the damaged part of the central nervous system. © 2003 Wiley‐Liss, Inc.
Effect of tranexamic acid incorporated in fibrin sealant clots on the cell behavior of neuronal and nonneuronal cells
Authors: Cox S. , Cole M. , Mankarious S. , Tawil N. 
Published: May 2003

AbstractFibrin sealants are commonly used for hemostasis following surgery on various types of tissues. Aprotinin, an effective fibrinolysis inhibitor, is one of the components in some fibrin sealant products currently available. Tranexamic acid (tAMCHA) is another fibrinolysis inhibitor and is used as an alternative to aprotinin. Recent studies on fibrin sealant products containing tAMCHA indicate that it may be responsible for various adverse reactions when used in neurological applications. To determine a possible mechanism for such adverse reactions, we examined the effect of tAMCHA on the behavior of neuronal and nonneuronal cells using in vitro assays. The data indicate that different concentrations of tAMCHA incorporated in fibrin clots had no effect on the initial cell adhesion of either proliferative cells (glial cells and fibroblasts) or nonproliferative cells (neuronal cells) to the fibrin clots. Moreover, a high concentration of tAMCHA (300–450 mM) incorporated in the fibrin clots increased glial and fibroblast proliferation on fibrin clots. However, because tAMCHA is known to leach out of the fibrin clots, we have also examined the effect of solubilized tAMCHA in a growth medium on cells seeded on matrix‐coated surfaces. A high concentration (300–450 mM) of tAMCHA detached all cell types from matrix‐coated dishes. Our model suggests that tAMCHA in fibrin clots has no adverse effect on cells bound to the fibrin clots; however, tAMCHA leaching out from the fibrin clots reduces adhesion of adjacent cells bound to their natural extracellular matrix. Thus, a high concentration of tAMCHA should not be used as a fibrinolysis inhibitor in fibrin sealant products, especially in neurosurgery. © 2003 Wiley‐Liss, Inc.
Overexpression of V‐1 prevents nitric oxide‐induced cell death: Involvement of enhanced tetrahydrobiopterin biosynthesis
Authors: Yuyama Kohei , Yamamoto Hideko , Nakamura Kazuhiro , Nishizaki Itone , Yamakuni Tohru , Song Si‐Young , Sora Ichiro , Nagatsu Toshiharu , Yamamoto Toshifumi 
Published: May 2003

AbstractPreviously we reported that the synthesis of catecholamines, dopamine, and noradrenaline was enhanced by overexpression of V‐1 protein, a neuronal protein active in the initial stage of development of the rat cerebellum, in the neuronal cell line PC12D, a model of dopamine cells (Yamakuni et al. [1998] J. Biol. Chem. 273:27051–27054). To investigate the physiological role of this protein, we examined the effect of V‐1 overexpression on cell toxicity induced by nitric oxide (NO) used at low concentrations. Two clones of PC12D cells overexpressing V‐1, transfectants termedV1‐46andV1‐69, were significantly more resistant to NOR3 (an NO donor) but not to etoposide (an inhibitor of topoisomerase II)‐induced apoptotic cell death than the control cells (termedC‐7andC‐9) that had been transfected with the vector alone. The addition of L‐DOPA, dopamine, or noradrenaline to the medium did not abolish NOR3‐induced cell death in PC12D cells. Moreover, pretreatment of V1‐46 and V1‐69 cells with L‐α‐methyl‐p‐tyrosine (α‐MPT), an inhibitor of tyrosine hydroxylase, to inhibit catecholamine biosynthesis did not affect the resistance to NO toxicity. These results indicate that the catecholamine levels increased by V‐1 overexpression did not produce the protection against NOR3‐induced toxicity. We further showed that overexpression of V‐1 enhanced the synthesis of (6R)‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4). In addition, pretreatment with BH4or with sepiapterin, which is converted to BH4intracellularly, significantly protected PC12D cells in a dose‐dependent manner. The increased BH4synthesis by V‐1 overexpression was dose dependently inhibited by pretreatment with diaminohydroxypyrimidine (DAHP), an inhibitor of GTP‐cyclohydrolase I, which is the rate‐limiting enzyme for the biosynthesis of BH4, concomitantly with the loss of protective effect afforded by V‐1 overexpression. Furthermore, the addition of BH4or sepiapterin to DAHP‐pretreated V146 and V1‐69 cells restored cell viability. Taken together, these results indicate that V1 protein plays an important role in protection against cell death induced by NO at low levels by promoting the synthesis of BH4. Moreover, these findings suggest the up‐regulation of V1 expression as a possible therapeutic target for protection against the insult of NO‐induced oxidative stress. © 2003 Wiley‐Liss, Inc.
Expression of depolarization‐induced immediate early gene proteins in PC12 cells
Authors: Liu Wei , Feldman Jonathan D. , Machado Hidevaldo B. , Vician Linda J. , Herschman Harvey R. 
Published: May 2003

AbstractImmediate early genes induced by depolarization are thought to be important in mediating neuronal functional plasticity. We previously identified a group of immediate early genes that are preferentially induced by depolarization and forskolin but not by nerve growth factor or epidermal growth factor in PC12 pheochromocytoma cells. These depolarization‐induced genes include synaptotagmin 4; the protein kinases KID‐1, PIM‐1, and SIK; an orphan transcription factor, Nurr‐1; and a transcription corepressor, rTLE‐3. All these genes are also induced in the hippocampus in response to kainic‐acid induced depolarization. To characterize further the unique functions of these genes in plasticity, we used recombinant proteins to generate and purify antibodies against KID‐1 and SIK proteins. Immunoblotting experiments were performed to examine the induced expression of the KID‐1 and SIK proteins in PC12 cells. PIM‐1 and Nurr‐1 protein expression was also examined following stimulation, using commercially available antibodies. There is an increase in synthesis, in PC12 cells, of these four IEG proteins after KCl plus forskolin treatment. Nurr‐1 protein peaks between 2 and 4 hr and decreases by 6 hr after the treatment. PIM‐1 and KID‐1 proteins rise by 1 hr, peak between 2 and 4 hr, and return to their basal levels at 6 hr. SIK protein increases significantly at 2 hr after treatment, peaks between 4 and 6 hr, and returns to the basal level at 8 hr. Immunofluorescence studies demonstrate distinct distribution patterns of each of these depolarization‐induced IEG proteins in PC12 cells. © 2003 Wiley‐Liss, Inc.
Oligodendrocyte progenitor migration in response to injury of glial monolayers requires the polysialic neural cell‐adhesion molecule
Authors: Barral‐Moran M.‐J. , Calaora V. , Vutskits L. , Wang C. , Zhang H. , Durbec P. , Rougon G. , Kiss J.Z. 
Published: May 2003

AbstractInjury to the nervous system results in reactive astrogliosis that is a critical determinant of neuronal regeneration. To analyze glial responses to mechanical injury and the role of the polysialic neural cell adhesion molecule (PSA‐NCAM) in this process, we established primary glia cultures from newborn rat cerebral cortex. Scratching a confluent monolayer of primary glial cells resulted in two major events: rapid migration of oligodendrocyte progenitor‐like (O‐2A) cells into the wounded area and development of polarized morphology of type 1 astrocytes at the wound edge. Migrating O‐2A progenitors had a bipolar morphology and exhibited A2B5 and O4 immunolabeling. Once these cells were established inside the wounded area, they lost A2B5 immunoreactivity and differentiated into glial fibrillary acidic protein‐positive astrocytes. Migrating O‐2A cells expressed PSA‐NCAM, but type 1 astrocytes at the wound edge did not. Treatment of wounded cultures with Endo‐N, which specifically removes PSA from the surface of cells, resulted in a significant decrease in O‐2A cell migration into the wounded area and completely blocked the wound closure. Video time‐lapse analysis showed that, in the presence of Endo‐N, O‐2A cells remained motile and migrated short distances but did not move away from the monolayer. These results demonstrate that O‐2A progenitors contribute to reactive astrogliosis in culture and that PSA‐NCAM is involved in this process by regulating cell migration. © 2003 Wiley‐Liss, Inc.
Grafted swine neuroepithelial stem cells can form myelinated axons and both efferent and afferent synapses with xenogeneic rat neurons
Authors: Uchida Koichi , Okano Hideyuki , Hayashi Takuro , Mine Yutaka , Tanioka Yoshikuni , Nomura Tatsuji , Kawase Takeshi 
Published: May 2003

AbstractNeuroepithelial stem cells derived from the swine mesencephalic neural tube were examined regarding their eligibility for neural xenografting as a donor material, with the aim of evaluating myelinated axon formation and both types of synaptic formation with xenogeneic host neurons as part of possible neural circuit reconstruction. The mesencephalic neural tube tissues were dissected out from swine embryos at embryonic days 17 and 18 and were implanted immediately into the striatum of the Parkinsonian model rat. The swine‐derived grafts had many nestin‐positive rosette‐forming, neurofilament‐positive, and tyrosine hydroxylase‐positive cells in the rat striatum. Electron microscopic study revealed both efferent and afferent synaptic formations in the donor‐derived immature neurons or tyrosine hydroxylase‐positive donor cells in the grafts. Myelinated axons, both positive and negative for swine‐specific neurofilament antibody, were mingled together in the graft. These results indicated that implanted neuroepithelial stem cells could survive well and divide asymmetrically into both nestin‐expressing precursors and differentiated neurochemical marker‐expressing neurons in the xenogeneic rat striatum, with the help of an immunosuppressant. Donor‐derived immature neurons formed both efferent and afferent synapses with xenogeneic host neurons, and donor‐derived axons were myelinated, which suggests that implanted swine neuroepithelial stem cells could possibly restore damaged neuronal circuitry in the diseased brain. © 2003 Wiley‐Liss, Inc.
Cyclic AMP responsive element binding protein phosphorylation and persistent expression of levodopa‐induced response alterations in unilateral nigrostriatal 6‐OHDA lesioned rats
Authors: Oh Justin D. , Chartisathian Karnon , Ahmed Syed M. , Chase Thomas N. 
Published: May 2003

AbstractActivation of cAMP responsive element binding protein (CREB) has been increasingly implicated in the formation and maintenance of long‐term memory. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa (L‐dopa) treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the activation of striatal CREB in 6‐hydroxydopamine (6‐OHDA) lesioned animals. Three weeks of twice‐daily L‐dopa treatment reduced the duration of the rotational response to acute L‐dopa challenge in hemiparkinsonian rats, which lasted about 5 weeks after withdrawal of chronic L‐dopa therapy. This shortened response duration, resembling human wearing‐off fluctuations, was associated with a marked increase in Ser‐133 phosphorylated CREB (pCREB) immunoreactivity in medium spiny neurons in dorsolateral striatum in response to acute dopaminomimetic challenge. Intermittent treatment with the D1 receptor‐preferring agonist SKF 38393, but not the D2 receptor‐preferring agonist quinpirole, produced a similar rise in CREB phosphorylation. The time course of changes in CREB phosphorylation correlated with the time course of changes in motor behavior after cessation of chronic L‐dopa therapy. Both the altered motor response duration and the degree of CREB phosphorylation were attenuated by the intrastriatal administration of CREB antisense or protein kinase A inhibitor Rp‐cAMPS. The results suggest that region‐specific Ser‐133 CREB phosphorylation in D1 receptor containing spiny neurons contributes to the persistence of the motor response alterations produced by intermittent stimulation of striatal dopaminergic receptors. © 2003 Wiley‐Liss, Inc.
Transcription profiling reveals mitochondrial, ubiquitin and signaling systems abnormalities in postmortem brains from subjects with a history of alcohol abuse or dependence
Authors: Sokolov Boris P. , Jiang Lixin , Trivedi Niraj S. , Aston Christopher 
Published: May 2003

AbstractAlcohol abuse is a common human disorder with high rate of comorbidity with other psychiatric disorders. To identify candidate mechanisms for alcohol abuse, the expression of 12,626 genes was measured in postmortem temporal cortex from 11 subjects with a history of alcohol abuse or dependence, with or without other psychiatric diagnoses and compared pairwise with the expression in 11 nonalcoholic subjects matched for the other psychiatric diagnoses and demographics. Genes were defined to have altered expression in alcohol abuse if: 1) the gene showed decreased expression in at least 10 of 11 subjects with alcohol abuse, or showed increased expression in at least 10 of 11 subjects with this diagnosis compared to matched non‐abusers (P < 0.007, χ2test); or 2) the difference in the mean abuser/non‐abuser ratio for the gene from value of 1.0 was significant at P < 0.05 (one sample t‐test). In subjects with a history of alcohol abuse or dependence, 163 genes were changed significantly. The most abundant and consistent changes were in gene families encoding mitochondrial proteins, the ubiquitin system, and signal transduction. These alterations indicate disturbances in energy metabolism and multiple signaling mechanisms in the temporal cortex of subjects with a history of alcohol abuse or dependence. We hypothesize that these mechanisms may be related to alcohol abuse traits or long‐term effects of alcohol. © 2003 Wiley‐Liss, Inc.
Understanding strategies for the improvement of inter‐organizational performance: cases from the air transport industry
Authors: Saxton Peter J. , Korac‐Kakabadse Nada 
Published: May 2003

AbstractIn the increasingly globalized economy there can be few organizations that have no need to interact with other organizations. In modern business, interaction with other organizations is virtually unavoidable. The ability to manage inter‐organizational affairs effectively might be a capability critical to the success of the organization.This paper presents an enquiry into inter‐organizational management. The aim of the enquiry was to identify and understand strategies that might improve inter‐organizational performance with monopoly suppliers, a context often seen as particularly difficult by practitioners and managers.The central purpose was to discover whether there exist any principles that might be generally applied by managers to improve the performance of inter‐organizationally managed processes. The research is based on two case studies of the management of baggage systems, one at London Heathrow Airport and the second at London Gatwick Airport.The Heathrow case was selected as an example of an operation where successful cooperation had been achieved. Gatwick was selected as a comparison because the cooperation within this operation was problematic. The paper concludes that there are principles that can be applied to different circumstances to improve inter‐organizational performance. Copyright © 2003 John Wiley &Sons, Ltd.