bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of NMDA receptor function by cyclic AMP in cerebellar neurones in culture
Authors: Llansola Marta , Sánchez‐Pérez Ana M. , Montoliu Carmina , Felipo Vicente 
Published: October 2004

AbstractThe signal transduction pathways involved in NMDA receptor modulation by other receptors remain unclear. cAMP could be involved in this modulation. The aim of this work was to analyse the contribution of cAMP to NMDA receptor modulation in cerebellar neurones in culture. Forskolin increases cAMP and results in increased intracellular calcium and cGMP that are prevented by blocking NMDA receptors. Similar effects were induced by two cAMP analogues, indicating that cAMP leads to NMDA receptor activation. It has been reported that phosphorylation of Ser897 of the NR1 subunit of NMDA receptors by cAMP‐dependent protein kinase (PKA) activates the receptors. Forskolin increases Ser897 phosphorylation. Neither Ser897 phosphorylation nor cGMP increase induced by forskolin are prevented by four inhibitors of PKA, suggesting that NMDA receptor activation is dependent on cAMP but not on PKA. Inhibition of Akt prevents forskolin‐induced phosphorylation of Ser897, suggesting a role for Akt in the mediation of the modulation of NMDA receptors by cAMP. Pituitary adenylate cyclase‐activating polypeptide (PACAP) activates its receptors, increasing cAMP and also leading to phosphorylation of Ser897 of NR1 and activation of NMDA receptors. These results indicate that cAMP modulates NMDA receptor in cerebellar neurones and may play a role in NMDA receptor modulation by other receptors.
Differential modulation of evoked and spontaneous glycine release from rat spinal cord glycinergic terminals by the cyclic AMP/protein kinase A transduction cascade
Authors: Katsurabayashi Shutaro , Kubota Hisahiko , Moorhouse Andrew J. , Akaike Norio 
Published: October 2004

AbstractThe mechanisms underlying cyclic AMP modulation of action potential‐dependent and ‐independent (spontaneous) release of glycine from terminals synapsing onto sacral dorsal commissural nucleus neurons of lamina X were studied in spinal cord slices using conventional patch‐clamp recordings. 3‐Isobutyl‐1‐methylxanthine (IBMX), a phosphodiesterase inhibitor, and forskolin increased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs) in a sensitive manner to protein kinase A (PKA) inhibition (with KT‐5720). Direct activation (with adenosine 3′,5′‐cyclic‐monophosphothioate, Sp‐isomer) and inhibition (with adenosine 3′,5′‐cyclic‐monophosphothioate, Rp‐isomer) of PKA increased and decreased the eIPSC amplitude, respectively. Paired pulse experiments and direct injection of PKA inhibitor fragment 6–22 amide (PKI6−22) into the recording neuron revealed that these effects on eIPSC amplitude occurred presynaptically, indicating that evoked glycine release is regulated by presynaptic cAMP via changes in PKA activity. Increasing cAMP also increased spontaneous release of glycine, causing an increased frequency of miniature IPSCs (mIPSCs). In contrast to the effects on evoked release, this response was not solely mediated via PKA, as it was not occluded by PKA inhibition, and both direct inhibition and direct activation of PKA actually enhanced mIPSC frequency. Direct inhibition of cAMP (with SQ 22536) did, however, reduce mIPSC frequency. These results suggest cAMP modulation of evoked and spontaneous release involves different presynaptic mechanisms and proteins.
Role of extracellular signal‐regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures
Authors: De Bernardo S. , Canals S. , Casarejos M. J. , Solano R. M. , Menendez J. , Mena M. A. 
Published: October 2004

AbstractTo date, glutathione (GSH) depletion is the earliest biochemical alteration shown in brains of Parkinson's disease patients, but the role of GSH in dopamine cell survival is debated. In this study we show that GSH depletion, produced with GSH synthesis inhibitor, l‐buthionine‐(S,R)‐sulfoximine (BSO), induces selectively neuronal cell death in neuron/glia, but not in neuronal‐enriched midbrain cultures and that cell death occurs with characteristics of necrosis and apoptosis. BSO produces a dose‐ and time‐dependent generation of reactive oxygen species (ROS) in neurons. BSO activates extracellular signal‐regulated kinases (ERK‐1/2), 4 and 6 h after treatment. MEK‐1/2 and lipoxygenase (LOX) inhibitors, as well as ascorbic acid, prevent ERK‐1/2 activation and neuronal loss, but the inhibition of nitric oxide sintase (NOS), cyclo‐oxygenase (COX), c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase (p38 MAPK) does not have protective effects. Co‐localization studies show that p‐ERK‐1/2 expression after BSO treatment increased in astrocytes and microglial cells, but not in neurons. Selective metabolic impairment of glial cells with fluoroacetate decreased ERK activation. However, blockade of microglial activation with minocycline did not. Our results indicate that neuronal death induced by GSH depletion is due to ROS‐dependent activation of the ERK‐1/2 signalling pathway in glial cells. These data may be of relevance in Parkinson's disease, where GSH depletion and glial dysfunction have been documented.
Autoreceptor‐mediated inhibition of norepinephrine release in rat medial prefrontal cortex is maintained after chronic desipramine treatment
Authors: Garcia April S. , Barrera Gabe , Burke Teresa F. , Ma Shuaike , Hensler Julie G. , Morilak David A. 
Published: October 2004

AbstractAlterations in noradrenergic neurotransmission are important in the mechanism of action of many antidepressant drugs, including selective norepinephrine (NA) reuptake inhibitors such as desipramine (DMI). It has been suggested that chronic NA reuptake blockade induces a desensitization of inhibitory α2‐adrenergic autoreceptors. This hypothesis was tested in experiment 1 using in vivo microdialysis to examine the degree of α2‐autoreceptor‐mediated inhibition of NA release in rat medial prefrontal cortex exerted by endogenous NA following chronic treatment with vehicle or DMI. This was accomplished by measuring the elevation of extracellular NA levels induced by acute administration of the α2‐receptor antagonist yohimbine. An 8‐fold increase in basal NA levels was observed after 21 days of DMI treatment. Further, acute yohimbine administration induced a robust elevation in NA levels which was not attenuated, and in fact at lower doses was greater in DMI‐treated rats compared with vehicle‐treated controls. In experiment 2, we addressed directly the functional status of terminal α2‐autoreceptors in frontal cortex in vitro, in the absence of potentially confounding competition from elevated levels of endogenous NA, after chronic reuptake blockade. We observed no difference in the degree to which the α2‐receptor agonist clonidine inhibited potassium‐evoked [3H]‐NA release from cortical slices taken from DMI‐ or vehicle‐treated rats. Together, these data suggest that endogenous activation of α2‐autoreceptors persists in restraining NA neurotransmission in the face of tonically elevated basal NA levels following chronic reuptake blockade.
Septin 3 (G‐septin) is a developmentally regulated phosphoprotein enriched in presynaptic nerve terminals
Authors: Xue Jing , Tsang Christopher W. , Gai Wei‐Ping , Malladi Chandra S. , Trimble William S. , Rostas John A. P. , Robinson Phillip J. 
Published: October 2004

AbstractThe septins are GTPase enzymes with multiple roles in cytokinesis, cell polarity or exocytosis. The proteins from the mammalian septin genes are called Sept1–10. Most are expressed in multiple tissues, but the mRNA for Sept5 (CDCrel‐1) and Sept3 (G‐septin) appear to be primarily expressed in brain. Sept3 is phosphorylated by cGMP‐dependent protein kinase I (PKG‐I) and the cGMP/PKG pathway is involved in presynaptic plasticity. Therefore to determine whether Sept3 specifically associates with neurones and nerve terminals we investigated its distribution in rat brain and neuronal cultures. Sept3 protein was detected only in brain by immunoblot, but not in 12 other tissues examined. Levels were high in all adult brain regions, and reduced in those enriched in white matter. Expression was developmentally regulated, being absent in the early embryo, low in late embryonic rat brain and increasing after birth. Like dynamin I, Sept3 was specifically enriched in synaptosomes compared with whole brain, and was only found in a peripheral membrane extract and not in the soluble or membrane extracts. Sept3 was particularly abundant in mossy fibre nerve terminals in the hippocampus. In primary cultured hippocampal neurones Sept3 immunoreactivity was punctate in neurites and predominantly localized to presynaptic terminals, strongly colocalizing with synaptophysin and dynamin I. The specific nerve terminal localization was confirmed by immunogold electron microscopy. Together this shows that Sept3 is a neurone‐specific protein highly enriched in nerve terminals which supports a secretory role in synaptic vesicle recycling.
Pyrrolidine dithiocarbamate inhibits translocation of nuclear factor kappa‐B in neurons and protects against brain ischaemia with a wide therapeutic time window
Authors: Nurmi Antti , Vartiainen Nina , Pihlaja Rea , Goldsteins Gundars , Yrjänheikki Juha , Koistinaho Jari 
Published: October 2004

AbstractPyrrolidine dithiocarbamate (PDTC) is an antioxidant and inhibitor of transcription factor nuclear factor kappa‐B (NF‐κB). Because the role of NF‐κB in brain injury is controversial and another NF‐κB inhibiting thiocarbamate, DDTC, was recently shown to increase ischaemic brain damage, we investigated the effect of PDTC on transient brain ischaemia. Ischaemia was induced by occlusion of the middle cerebral artery (MCAO). In Wistar rats, the PDTC treatment started even 6 h after MCAO reduced the infarction volume by 48%. PDTC protected against MCAO also in spontaneously hypertensive rats and against forebrain ischaemia in Mongolian gerbils. PDTC prevented NF‐κB activation in the ischaemic brain as determined by reduced DNA binding and nuclear translocation of NF‐κB in neurons. PDTC had anti‐inflammatory effect by preventing induction of NF‐κB‐regulated pro‐inflammatory genes. In ischaemic rats, NF‐κB was localized in cyclo‐oxygenase‐2‐immunoreactive neurons. Blood cytokine levels were not altered by ischaemia or PDTC. When cultured neurons were exposed to an excitotoxin, no production of reactive oxygen species was detected, but PDTC provided protection and prevented nuclear translocation of NF‐κB. The clinically approved PDTC and its analogues may act as anti‐inflammatories and may be safe therapies in stroke with a wide time window.
A role for semaphorin 3A signaling in the degeneration of hippocampal neurons during Alzheimer's disease
Authors: Good Paul F. , Alapat Daisy , Hsu Amy , Chu Caryn , Perl Daniel , Wen Xiaping , Burstein David E. , Kohtz D. Stave 
Published: October 2004

AbstractAmong the earliest invariant neuropathological changes in Alzheimer's disease (AD) is the degeneration of vulnerable hippocampal CA1 and subicular pyramidal neurons. Semaphorin 3A (Sema3A) is a secreted protein that functions in signaling growth cone collapse, chemorepulsion and neuronal apoptosis during early development of the central nervous system. In this report we show that accumulation of an internalized form of Sema3A is associated with degeneration of neurons in vulnerable fields of the hippocampus during AD. Accumulation of Sema3A overlaps the appearance of phosphorylated MAP1B and tau in many neurons, suggesting that Sema3A signaling at some level may be coupled to these previously identified cytoskeletal markers of neurodegeneration. Consistent with this, we isolated and partially characterized a multiprotein complex from the hippocampus of patients with AD that contains phosphorylated MAP1B, collapsin‐response mediator protein 2 (CRMP‐2), Plexins A1 and A2, and a processed form of Sema3A. A model is presented in which aberrant release of Sema3A from expressing neurons in the subiculum during AD results in the internalization and transport of Sema3A from this field to CA1. Within the context of the myriad of potential insults that contribute to Alzheimer's and other neurodegenerative diseases, the bioactivity of Sema3A may contribute either directly to neurodegeneration by inducing neuronal collapse, or indirectly by abrogating the recovery capabilities of adult neurons faced with these insults.
Nitric oxide‐induced increase of excitatory amino acid levels in the trigeminal nucleus caudalis of the rat with tactile hypersensitivity evoked by the loose‐ligation of the inferior alveolar nerves
Authors: Fujita Toyohiro , Kamisaki Yoshinori , Yonehara Norifumi 
Published: October 2004

AbstractTo investigate whether or not N‐methyl‐d‐aspartate (NMDA)/nitric oxide (NO) pathway in the trigeminal system is involved in the development and/or maintenance of such pathological pain states as the hyperalgesia and allodynia observed after dental surgery, we examined the alteration patterns of excitatory amino acid (EAA) level in the superficial layer of subnucleus caudalis of the brain‐stem trigeminal sensory nuclear complex (SpVc‐I,II) by in vivo microdialysis. A very high EAA release response was observed immediately after the start of the perfusion in ligated animals compared with sham‐operated rats. The EAA level evoked by application of the 40‐V tooth pulp‐stimulation or 1% capsaicin cream was significantly higher in the ligated animals than those in the sham‐operated animals. This increase of EAA level induced by capsaicin cream was inhibited by adding carboxy‐PTIO (100 µm) to the perfusate. The applications of SNAP (2 mm) into the perfusate enhanced the level of EAAs in ligated animals and sham‐operated animals. However, SNAP‐evoked EAA levels in ligated animals were not significantly different compared with those of sham‐operated animals. These results suggest that alterations in the stimulus‐evoked raised EAA levels that occur in the site of the first synaptic relay of the dental pain pathway and which are expressed via endogenous NO, and which play an important role in development and/or maintenance of pathological pain states following dental peripheral nerve injury.
Up‐regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease
Authors: Angulo Ester , Noé Véronique , Casadó Vicent , Mallol Josefa , Gomez‐Isla Teresa , Lluis Carmen , Ferrer Isidre , Ciudad Carlos J. , Franco Rafael 
Published: October 2004

AbstractGene expression throughout the different stages of Alzheimer's disease was analysed in samples from cerebral cortex. The gene encoding the voltage‐gated potassium channel Kv3.4 was already overexpressed in early stages of the disease, and in advanced stages Kv3.4 was present at high levels in neurodegenerative structures. This subunit regulates delayed‐rectifier currents, which are primary determinants of spike repolarization in neurones. In unique samples from a patient with Alzheimer's disease whose amount of amyloid plaques was decreased by β amyloid immunization, Kv3.4 was overexpressed. The channel subunit was expressed in the neuropil, in the remaining conventional plaques in the frontal cortex and in collapsed plaques in the orbitary cortex. Therefore, amyloid deposition in plaques does not seem to be responsible for the increase in Kv3.4 levels. Nevertheless, Kv3.4 up‐regulation is related to amyloid pathology, given that transgenic mice with the Swedish mutation of amyloid precursor protein showed increased expression of Kv3.4. Up‐regulation of voltage‐gated potassium channel subunits alters potassium currents in neurones and leads to altered synaptic activity that may underlie the neurodegeneration observed in Alzheimer's disease. Thus, Kv3.4 likely represents a novel therapeutic target for the disease.
Minocycline inhibits apoptotic cell death via attenuation of TNF‐α expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co‐cultures
Authors: Lee Sang M. , Yune Tae Y. , Kim Sun J. , Kim Young C. , Oh Young J. , Markelonis George J. , Oh Tae H. 
Published: October 2004

AbstractWe attempted to ascertain the neuroprotective effects and mechanisms of minocycline in inflammatory‐mediated neurotoxicity using primary neuron/glia co‐cultures treated with lipopolysaccharide (LPS). Neuronal cell death was induced by treatment with LPS for 48 h, and the cell damage was assessed using lactate dehydrogenase (LDH) assays and by counting microtubule‐associated protein‐2 (MAP‐2) positive cells. Through terminal transferase deoxyuridine triphosphate‐biotin nick end labeling (TUNEL)‐staining and by measuring caspase‐3 activity, we found that LPS‐induced neuronal cell death was mediated by apoptosis. We determined that pre‐treatment with minocycline significantly inhibited LPS‐induced neuronal cell death. In addition, LPS induced inducible nitric oxide synthase (iNOS) expression significantly, resulting in nitric oxide (NO) production within glial cells, but not in neurons. Both nitric oxide synthase (NOS) inhibitors (NG‐monomethyl‐l‐arginine monoacetate (l‐NMMA) and S‐methylisothiourea sulfate (SMT)) and minocycline inhibited iNOS expression and NO release, and increased neuronal survival in neuron/glia co‐cultures. Pre‐treatment with minocycline significantly inhibited the rapid and extensive production of tumor necrosis factor‐alpha (TNF‐α) mediated by LPS in glial cells. We also determined that the signaling cascade of LPS‐mediated iNOS induction and NO production was mediated by TNF‐α by using neutralizing antibodies to TNF‐α. Consequently, our results show that the neuroprotective effect of minocycline is associated with inhibition of iNOS induction and NO production in glial cells, which is mediated by the LPS‐induced production of TNF‐α.
Signal‐Averaged P Wave Duration and the Dimensions of the Atria
Authors: Dixen Ulrik , Joens Christian , Rasmussen Bo V. , Parner Jan , Jensen Gorm B. 
Published: October 2004

Background: Delay of atrial electrical conduction measured as prolonged signal‐averaged P wave duration (SAPWD) could be due to atrial enlargement. Here, we aimed to compare different atrial size parameters obtained from echocardiography with the SAPWD measured with a signal‐averaged electrocardiogram (SAECG). Methods: In 74 patients scheduled for elective echocardiography, an SAECG was recorded directly after the echocardiogram. We measured the SAPWD and registered clinical characteristics. The correlation between the SAPWD and the left atrial diameter (LAD), left atrial volume (LAV), right atrial volume (RAV), and total atrial volume (TAV) was analyzed by linear regression analyses. The effect of concomitant risk factors on TAV and the SAPWD was examined. Results: Linear regression analysis showed that the correlation between the SAPWD and the LAD was significant (R2= 0.11, P = 0.03). However, LAV (R2= 0.15, P = 0.009), RAV (R2= 0.27, P = 0.0003), and TAV (R2= 0.37, P < 0.0001) were more strongly correlated to the SAPWD. The TAV and the SAPWD were not significantly associated with coexisting risk factors. Conclusions: The SAPWD is significantly correlated to the atrial size; most strongly to the TAV. The size of the right atrium, with the sinus node area, appears to affect the SAPWD.
Evaluation of Left Atrial Appendage Functions in Patients with Thrombus and Spontaneous Echo Contrast in Left Atrial Appendage by Using Color Doppler Tissue Imaging
Authors: Topsakal Ramazan , Eryol Namık Kemal , Çiçek Yüksel , Sağlam Hayrettin , Seyfeli Ergün , Abaci Adnan , Oğuzhan Abdurrahman , Ergin Ali , Başar Emrullah 
Published: October 2004

Objective: Thrombus and spontaneous echo contrast (SEC) develops in the left atrial appendage (LAA) when LAA function is disturbed. Decrease of left atrial appendage emptying velocity shows LAA dysfunction. The purpose of this study is to examine the incidence of SEC and/or thrombus in LAA in patients with acute myocardial infarction and to assess the LAA function using color Doppler tissue imaging (CDTI) of the patients with detected SEC and/or thrombus. Method and Results: Eighty‐four patients with acute myocardial infarction were included in the study. Spontaneous echo contrast and/or thrombus were observed in 24 (29%) of the 84 patients who were categorized as group 1 (mean age 59 ± 12 years). Sixty patients (71%) without thrombus and/or SEC in LAA were categorized as group 2 (mean age 58 ± 8 years). Left atrial diameters and left ventricular ejection fraction were measured by using transthoracic echocardiography. Left atrial appendage emptying and LAA filling velocity were measured by transesophageal Doppler echocardiography. Systolic appendage tissue velocities (SaV cm/s) were measured at the basal, mid, and tip of medial wall of LAA by transesophageal CDTI. Group 1 had significantly decreased LAA emptying velocities, mid SaVs, and left ventricular ejection fractions compared to group 2 (37 ± 9 cm/s vs 55 ± 22 cm/s, 3.1 ± 1.6 cm/s vs 3.7 ± 1.2 cm/s, and 47 ± 13% vs 58 ± 10%, respectively, P = 0.002, P = 0.04, P = 0.03). Group 1 had significantly increased left atrial diameters compared to group 2 (40 ± 5 mm vs 36 ± 6 mm P = 0.001). Left atrial appendage‐filling velocities, basal SaVs and tip SaVs in group 1 were lower than those in group 2 but not significantly. Conclusions: Mid‐SaV of LAA medial wall and LAA emptying velocity decrease in patients with thrombus and/or SEC were an indication of functional disorder of LAA. Color Doppler tissue imaging appears to be a clinically applicable and reliable imaging technique that allows quantitative assessment of regional LAA systolic function.
Why a Sawtooth? Inferences on the Generation of the Flutter Wave during Typical Atrial Flutter Drawn from Radiofrequency Ablation
Authors: Bernstein Neil E. , Sandler David A. , Goh Mark , Feigenblum David Y. , Holmes Douglas S. , Chinitz Larry A. 
Published: October 2004

Background: Typical atrial flutter (AFL) is a macroreentrant arrhythmia characterized by a counterclockwise circuit that passes through the cavotricuspid isthmus with passive depolarization of the left atrium. These electrical events are thought to be responsible for the classic “sawtooth” wave of atrial flutter seen on the surface electrocardiogram characterized by a gradual downward deflection followed by a sharp negative deflection. It has been suggested that the negative flutter wave is a result of passive depolarization of the left atrium. We hypothesized that interruption of the circuit within the isthmus would prevent the reentrant wave from depolarizing the left atrium thus eliminating the component of the electrocardiogram reflecting left atrial depolarization. Methods: We examined 100 cases of atrial flutter with the typical “sawtooth” pattern referred for radiofrequency ablation. Ninety‐seven of the 100 were successfully ablated. All cases were reviewed for termination of atrial flutter with the last intracardiac electrogram just lateral to the site of linear ablation and surface flutter wave at the moment of termination not obscured by the QRS segment or the T‐wave. Seventeen of the 97 met these criteria. Results: Seventeen of the 17 cases demonstrated a gradual negative deflection as the last discernible wave of atrial activity followed by an isoelectric period and resumption of normal sinus rhythm. The last generated wave lacked the sharp negative downstroke. Conclusion: These results suggest that the sharp negative deflection of flutter waves likely correlates with the wavefront's penetration of the interatrial septum and passive depolarization of the left atrium.