bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ectopic decorin expression up‐regulates VEGF expression in mouse cerebral endothelial cells via activation of the transcription factors Sp1, HIF1α, and Stat3
Authors: Santra Manoranjan , Santra Sutapa , Zhang Jing , Chopp Michael 
Published: March 2008

AbstractWe demonstrate that a proteoglycan decorin (DCN) up‐regulates the vascular endothelial growth factor (VEGF) expression with activation of VEGF regulating transcription factors Sp1, hypoxia‐inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (Stat3) via epidermal growth factor receptor (EGFR), mitogen‐activated protein kinase extracellular signal‐regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT) pathways in DCN transfected mouse cerebral endothelial (MCE) cells. Treatment with pharmacological inhibitors and small interfering RNAs reveal that induction and activation of Sp1, HIF1α, and Stat3 facilitate their nuclear localization and binding to their specific motifs of the VEGF promoter and induce VEGF expression via two independent pathways, DCN/EGFR/phosphoinositide‐3 kinase/AKT and DCN/EGFR/ERK1/2, respectively, in DCN synthesizing MCE cells. The cell type specific glycosylation protects Sp1 and HIF1α from proteosome degradation and plays an important and novel role in the regulation of VEGF in DCN transfected MCE cells. Induction of gelatinases (matrix metalloproteinase 2 and 9), the serine protease tissue plasminogen activator and plasmin by DCN transfection in MCE cells leads to extracellular proteolysis and to release of matrix‐bound VEGF and activation of angiogenesis. In this study, we demonstrate that two independent downstream signal pathways, DCN/EGFR/ERK1/2 and DCN/EGFR/phosphoinositide‐3 kinase/AKT, mediate up‐regulation and activation of transcription factors of VEGF such as HIF1α, Stat3, and Sp1 and increase VEGF transcription and angiogenesis in MCE cells.
Role of tissue plasminogen activator in the sensitization of methamphetamine‐induced dopamine release in the nucleus accumbens
Authors: Fukakusa Ayumi , Nagai Taku , Mizoguchi Hiroyuki , Otsuka Noboru , Kimura Haruhide , Kamei Hiroyuki , Kim Hyoung‐Chun , Nabeshima Toshitaka , Takuma Kazuhiro , Yamada Kiyofumi 
Published: March 2008

AbstractWe have previously demonstrated that repeated, but not acute, methamphetamine (METH) treatment increases tissue plasminogen activator (tPA) activity in the brain, which is associated with the development of behavioral sensitization to METH. In this study, we investigated whether the tPA‐plasmin system is involved in the development of sensitization in METH‐induced dopamine release in the nucleus accumbens (NAc). There was no difference in acute METH‐induced increase in extracellular dopamine levels in the NAc between wild‐type and tPA‐deficient (tPA−/−) mice. Repeated METH treatment resulted in a significant enhancement of METH‐ induced dopamine release in wild‐type mice, but not tPA−/− mice. Microinjection of exogenous tPA or plasmin into the NAc of wild‐type mice significantly potentiated acute METH‐ induced dopamine release. Degradation of laminin was evident in brain tissues incubated with tPA plus plasminogen or plasmin in vitro although tPA or plasminogen alone had no effect. Immunohistochemical analysis revealed that microinjection of plasmin into the NAc reduced laminin immunoreactivity without neuronal damage. Our findings suggest that the tPA‐plasmin system participates in the development of behavioral sensitization induced by repeated METH treatment, by regulating the processes underlying the sensitization of METH‐induced dopamine release in the NAc, in which degradation of laminin by plasmin may play a role.
Lysophosphatidic acid‐LPA1receptor–Rho–Rho kinase‐induced up‐regulation of Nav1.7 sodium channel mRNA and protein in adrenal chromaffin cells: enhancement of22Na+influx,45Ca2+influx and catecholamine secretion
Authors: Maruta Toyoaki , Yanagita Toshihiko , Matsuo Kiyotaka , Uezono Yasuhito , Satoh Shinya , Nemoto Takayuki , Yoshikawa Norie , Kobayashi Hideyuki , Takasaki Mayumi , Wada Akihiko 
Published: March 2008

AbstractIn cultured bovine adrenal chromaffin cells, chronic (≥ 24 h) treatment with lysophosphatidic acid (LPA) augmented veratridine‐induced22Na+influx via Nav1.7 by ∼22% (EC50 = 1 nmol/L), without changing nicotine‐induced22Na+influx via nicotinic receptor‐associated channel. LPA enhanced veratridine (but not nicotine)‐induced45Ca2+influx via voltage‐dependent calcium channel and catecholamine secretion. LPA shifted concentration–response curve of veratridine for22Na+influx upward, without altering the EC50of veratridine.Ptychodiscus brevistoxin‐3 allosterically enhanced veratridine‐induced22Na+influx by twofold in non‐treated and LPA‐treated cells. Whole‐cell patch‐clamp analysis showed that peak Na+current amplitude was greater by 39% in LPA (100 nmol/L for 36 h)‐treated cells; however,I–Vcurve and steady‐state inactivation/activation curves were comparable between non‐treated and LPA‐treated cells. LPA treatment (≥ 24 h) increased cell surface [3H]saxitoxin binding by ∼28%, without altering theKdvalue; the increase was prevented by cycloheximide, actinomycin D, or Ki16425, dioctylglycerol pyrophosphate 8:0 (two inhibitors of LPA1and LPA3receptors), or botulinum toxin C3 (Rho inhibitor), Y27632 (Rho kinase inhibitor), consistent with LPA1receptor expression in adrenal chromaffin cells. LPA raised Nav1.7 mRNA level by ∼37%. Thus, LPA–LPA1receptor–Rho/Rho kinase pathway up‐regulated cell surface Nav1.7 and Nav1.7 mRNA levels, enhancing veratridine‐induced Ca2+influx and catecholamine secretion.
Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine
Authors: Weinshenker David , Ferrucci Michela , Busceti Carla L. , Biagioni Francesca , Lazzeri Gloria , Liles L. Cameron , Lenzi Paola , Pasquali Livia , Murri Luigi , Paparelli Antonio , Fornai Francesco 
Published: March 2008

AbstractN‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP‐4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β‐hydroxylase; DBH). We found that genetic deletion of DBH (DBH−/− mice) and acute treatment of wild‐type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP‐4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured byin vivomicrodialysis of DA and 2,3‐dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.
The newly synthesized pool of dopamine determines the severity of methamphetamine‐induced neurotoxicity
Authors: Thomas David M. , Francescutti‐Verbeem Dina M. , Kuhn Donald M. 
Published: March 2008

AbstractThe neurotransmitter dopamine (DA) has long been implicated as a participant in the neurotoxicity caused by methamphetamine (METH), yet, its mechanism of action in this regard is not fully understood. Treatment of mice with the tyrosine hydroxylase (TH) inhibitor α‐methyl‐p‐tyrosine (AMPT) lowers striatal cytoplasmic DA content by 55% and completely protects against METH‐induced damage to DA nerve terminals. Reserpine, by disrupting vesicle amine storage, depletes striatal DA by more than 95% and accentuates METH‐induced neurotoxicity.l‐DOPA reverses the protective effect of AMPT against METH and enhances neurotoxicity in animals with intact TH. Inhibition of MAO‐A by clorgyline increases pre‐synaptic DA content and enhances METH striatal neurotoxicity. In all conditions of altered pre‐synaptic DA homeostasis, increases or decreases in METH neurotoxicity paralleled changes in striatal microglial activation. Mice treated with AMPT,l‐DOPA, or clorgyline + METH developed hyperthermia to the same extent as animals treated with METH alone, whereas mice treated with reserpine + METH were hypothermic, suggesting that the effects of alterations in cytoplasmic DA on METH neurotoxicity were not strictly mediated by changes in core body temperature. Taken together, the present data reinforce the notion that METH‐induced release of DA from the newly synthesized pool of transmitter into the extracellular space plays an essential role in drug‐induced striatal neurotoxicity and microglial activation. Subtle alterations in intracellular DA content can lead to significant enhancement of METH neurotoxicity. Our results also suggest that reactants derived from METH‐induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH.
A novel cell death pathway that is partially caspase dependent, but morphologically non‐apoptotic, elicited by proteasomal inhibition of rat sympathetic neurons
Authors: Lang‐Rollin Isabelle , Dermentzaki Georgia , Vekrellis Kostas , Xilouri Maria , Rideout Hardy J. , Stefanis Leonidas 
Published: March 2008

AbstractProteasomal dysfunction has been linked to neurodegeneration. Pharmacological proteasomal inhibitors may have pro‐survival or pro‐death effects in neuronal cells. We have previously found that application of such agents to mouse sympathetic neurons leads to activation of the intrinsic apoptotic pathway. We show here that in rat sympathetic neurons proteasomal inhibition leads to a form of death that is morphologically non‐apoptotic, with features of autophagy. The intrinsic apoptotic pathway is activated in a delayed fashion compared with mouse neurons, and is in part responsible for death, as evidenced by the partial protective effects of bcl‐xL and the general caspase inhibitor Boc‐aspartyl‐fluoromethylketone. Death is accompanied by induction of Bim and caspase activation, but caspase 3 activation is lacking; 3‐methyl‐adenine inhibits macroautophagy, but has a relatively small pro‐survival effect. We conclude that a complex array of pro‐ and anti‐apoptotic effects elicited by proteasomal inhibition in rat sympathetic neurons leads to partial engagement of the intrinsic apoptotic pathway and a morphologically non‐apoptotic, autophagic form of death. The species difference with mouse neurons is underscored by the fact that proteasomal inhibitors are protective against apoptosis elicited by nerve growth factor deprivation in rat, but not mouse, sympathetic neurons. The type of death described herein may be relevant to neurodegenerative diseases, where morphological evidence for apoptosis has been scant.
SP1 regulates a human SNAP‐25 gene expression
Authors: Cai Fang , Chen Bin , Zhou Weihui , Zis Odysseus , Liu Shengchun , Holt Robert A. , Honer William G. , Song Weihong 
Published: March 2008

AbstractThe synaptosomal‐associated protein of 25 kDa (SNAP‐25) is a pre‐synaptic plasma membrane protein. SNAP‐25 plays an important role in synaptic vesicle membrane docking and fusion, which is involved in the regulation of neurotransmitter release. SNAP‐25 has been implicated in the pathogenesis of neuropsychiatric disorders including Schizophrenia, attention‐deficit hyperactivity disorder and Alzheimer’s disease. We cloned a 1584 bp segment of the 5′ flanking region of the human SNAP‐25 gene. A series of nested deletions of the 5′ flanking region fragment were subcloned into the pGL3‐basic luciferase reporter plasmid. N2A cells were transfected with the SNAP‐25 promoter constructs and luciferase activity was measured as an indication of promoter activity. We identified a 188 bp fragment containing the transcription initiation site as the minimal region necessary for promoter activity. Several putative cis‐acting elements including SP1, hypoxia inducible factor (HIF), cAMP‐response element binding protein, T‐cell factor/lymphocyte enhancer factor 1 (TCF/LEF1), AP1 and the signal transducer and activator of transcription‐6 (STAT6) are found in the 5′ flanking region of SNAP‐25 gene. Transcriptional activation and gel shift assays showed that the human SNAP‐25 gene promoter contains functional SP1 response elements. Over‐expression of SP1 increased SNAP‐25 gene expression and inhibition of SP1‐mediated transcriptional activation reduced SNAP‐25 gene expression. These results suggest that SP1 plays an important role in regulation of the human SNAP‐25 gene expression.
Targeting epileptogenesis‐associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development
Authors: Pekcec Anton , Fuest Christina , Mühlenhoff Martina , Gerardy‐Schahn Rita , Potschka Heidrun 
Published: March 2008

AbstractPolysialylation is a post‐translational modification of the neural cell adhesion molecule (NCAM), which in the adult brain promotes structural changes in regions of neurogenesis and neuroplasticity. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the polysialic acid (PSA)‐NCAM system on development of this disease and associated comorbidities. Therefore, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in an electrically induced rat post‐status epilepticus (SE) model. Loss of PSA counteracted the SE‐induced increase in neurogenesis in a significant manner. This effect of endoneuraminidase (endoN) treatment on hippocampal neurogenesis did not impact the subsequent development of spontaneous seizures. In contrast, transient lack of PSA during SE and in the early phase of epileptogenesis exhibited a cognition sparing effect as revealed in the Morris water maze paradigm. In conclusion, our data do not support a central role of neurogenesis in the development of a hyperexcitable epileptic network. However, in view of the cognition‐sparing effect, the transient modulation of the PSA‐NCAM system seems to allow beneficial long‐term disease modification, which might be mediated by the partial normalization of neurogenesis.
The Kv4.2 mediates excitatory activity‐dependent regulation of neuronal excitability in rat cortical neurons
Authors: Shen Bin , Zhou Kechun , Yang Shenglian , Xu Tianle , Wang Yizheng 
Published: March 2008

AbstractNeuronal excitability can cooperate with synaptic transmission to control the information storage. This regulation of neuronal plasticity can be affected by alterations in neuronal inputs and accomplished by modulation of voltage‐dependent ion channels. In this study, we report that enhanced excitatory input negatively regulated neuronal excitability. Enhanced excitatory input by glutamate, electric field stimulation or high K+ increased transient outward K+ current, whereas did not affect the delayed rectifier K+ current in rat cultured cortical neurons. Both the voltage‐dependent K+ channel 4.2 and 4.3 subunits contributed to the increase. The increase in the K+ current density by Kv4.2 was ascribed to its cytoplasmic membrane translocation, which was mediated by NMDA type of glutamate receptor. Furthermore, enhanced excitatory input inhibited neuronal excitability. Taken together, our results suggest that excitatory neurotransmission affects neuronal excitability via the regulation of the K+ channel membrane translocation.
STAT3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damage
Authors: Ueki Yumi , Wang Jiangang , Chollangi Srinivas , Ash John D. 
Published: March 2008

AbstractMembers of the interleukin‐6 cytokine family, including leukemia inhibitory factor (LIF), signal through gp130. The neuroprotective role of gp130 activation has been widely demonstrated in both CNS and PNS, but the mechanism by which this is accomplished is not well established. We investigated temporal and cell‐specific activation of signaling pathways induced by LIF in the mature mouse retina. Intravitreal injection of LIF preserved photoreceptor function and prevented photoreceptor cell death from light‐induced oxidative damage in a dose‐dependent manner (2 days post‐injection). A therapeutic dose of LIF induced rapid and sustained activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 was localized to all the retinal neurons and glial cells, including photoreceptors. Activation of extracellular signal‐regulated kinase 1 and 2 was robust but transient in Müller glial cells, and undetectable at the time of light exposure. Akt was not activated by LIF. We also show that at the time of neuroprotection, STAT3 but not extracellular signal‐regulated kinase 1 and 2 or the Akt pathways was active in LIF‐treated retinas, and activated STAT3 was clearly localized in transcriptionally active areas of photoreceptor nuclei. Our data suggest that photoreceptor protection in response to LIF can be directly mediated by activation of STAT3 in photoreceptors.
Calpain activation is involved in early caspase‐independent neurodegeneration in the hippocampus following status epilepticus
Authors: Araújo Inês M. , Gil Joana M. , Carreira Bruno P. , Mohapel Paul , Petersen Åsa , Pinheiro Paulo S. , Soulet Denis , Bahr Ben A. , Brundin Patrik , Carvalho Caetana M. 
Published: March 2008

AbstractEvidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (10 mg/kg) intraperitoneally and killed 24 h later, after development of grade 5 seizures. We observed a strong Fluoro‐Jade labeling in the CA1 and CA3 areas of the hippocampus in the rats that received kainic acid, when compared with saline‐treated rats. Immunohistochemistry and western blot analysis for the calpain‐derived breakdown products of spectrin showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
Modulation of peroxisome proliferator‐activated receptor‐α activity by N‐acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures
Authors: Paintlia Manjeet K. , Paintlia Ajaib S. , Khan Mushfiquddin , Singh Inderjit , Singh Avtar K. 
Published: March 2008

AbstractGlial cells secrete proinflammatory mediators in the brain in response to exogenous stimuli such as infection and injury. Previously, we documented that systemic maternal lipopolysaccharide (LPS)‐exposure at embryonic gestation day 18 causes oligodendrocyte (OL)‐injury/hypomyelination in the developing brain which can be attenuated by N‐acetyl cysteine (NAC; precursor of glutathione). The present study delineates the underlying mechanism of NAC‐mediated attenuation of inhibition of OL development in LPS‐stimulated mixed glial cultures. Factors released by LPS‐stimulated mixed glial cultures inhibited OL development as shown by decrease in both proliferation 3bromo‐deoxyuridine+/chondroitin sulfate proteoglycan–NG2+, hereafter BrdU+/NG+ and differentiation (O4+ and myelin basic protein+) of OL‐progenitors. Correspondingly, an impairment of peroxisomal proliferation was shown by a decrease in the level of peroxisomal proteins in the developing OLs following exposure to LPS‐conditioned media (LCM). Both NAC and WY14643, a peroxisome proliferator‐activated receptor (PPAR)‐α agonist attenuated these LCM‐induced effects in OL‐progenitors. Similar to WY14643, NAC attenuated LCM‐induced inhibition of PPAR‐α activity in developing OLs. Studies conducted with cytokines and diamide (a thiol‐depleting agent) confirmed that cytokines are active agents in LCM which may be responsible for inhibition of OL development via peroxisomal dysfunction and induction of oxidative stress. These findings were further corroborated by similar treatment of developing OLs generated from PPAR‐α(−/−) and wild‐type mice or B12 oligodendroglial cells co‐transfected with PPAR‐α small interfering RNAs/pTK‐PPREx3‐Luc plasmids. Collectively, these data provide evidence that the modulation of PPAR‐α activity, thus peroxisomal function by NAC attenuates LPS‐induced glial factors‐mediated inhibition of OL development suggesting new therapeutic interventions to prevent the devastating effects of maternal infections.
Aplysia synapse associated protein (APSAP): identification, characterization, and selective interactions with Shaker‐type potassium channels
Authors: Reissner Kathryn J. , Boyle Heather D. , Ye Xiaojing , Carew Thomas J. 
Published: March 2008

AbstractThe vertebrate post‐synaptic density (PSD) is a region of high molecular complexity in which dynamic protein interactions modulate receptor localization and synaptic function. Members of the membrane‐associated guanylate kinase (MAGUK) family of proteins represent a major structural and functional component of the vertebrate PSD. In order to investigate the expression and significance of orthologous PSD components associated with the Aplysia sensory neuron‐motor neuron synapse, we have cloned an Aplysia Dlg‐MAGUK protein, which we identify as Aplysia synapse associated protein (ApSAP). As revealed by western blot, RT‐PCR, and immunocytochemical analyses, ApSAP is predominantly expressed in the CNS and is located in both sensory neuron and motor neurons. The overall amino acid sequence of ApSAP is 55–61% identical to Drosophila Dlg and mammalian Dlg‐MAGUK proteins, but is more highly conserved within L27, PDZ, SH3, and guanylate kinase domains. Because these conserved domains mediate salient interactions with receptors and other PSD components of the vertebrate synapse, we performed a series of GST pull‐down assays using recombinant C‐terminal tail proteins from various Aplysia receptors and channels containing C‐terminal PDZ binding sequences. We have found that ApSAP selectively binds to an Aplysia Shaker‐type channel AKv1.1, but not to (i) NMDA receptor subunit AcNR1‐1, (ii) potassium channel AKv5.1, (iii) receptor tyrosine kinase ApTrkl, (iv) glutamate receptor ApGluR1/4, (v) glutamate receptor ApGluR2/3, or (vi) glutamate receptor ApGluR7. These findings provide preliminary information regarding the expression and interactions of Dlg‐MAGUK proteins of the Aplysia CNS, and will inform questions aimed at a functional analysis of how interactions in a protein network such as the PSD may regulate synaptic strength.