bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice
Authors: Lopez José R. , Lyckman Alvin , Oddo Salvatore , LaFerla Frank M. , Querfurth Henry W. , Shtifman Alexander 
Published: March 2008

AbstractNeurodegeneration in Alzheimer’s disease (AD) has been linked to intracellular accumulation of misfolded proteins and dysregulation of intracellular Ca2+. In the current work, we determined the contribution of specific Ca2+ pathways to an alteration in Ca2+ homeostasis in primary cortical neurons from an adult triple transgenic (3xTg‐AD) mouse model of AD that exhibits intraneuronal accumulation of β‐amyloid proteins. Resting free Ca2+ concentration ([Ca2+]i), as measured with Ca2+‐selective microelectrodes, was greatly elevated in neurons from 3xTg‐AD and APPSWE mouse strains when compared with their respective non‐transgenic neurons, while there was no alteration in the resting membrane potential. In the absence of the extracellular Ca2+, the [Ca2+]i returned to near normal levels in 3xTg‐AD neurons, demonstrating that extracellular Ca2+contributed to elevated [Ca2+]i. Application of nifedipine, or a non‐L‐type channel blocker, SKF‐96365, partially reduced [Ca2+]i. Blocking the ryanodine receptors, with ryanodine or FLA‐365 had no effect, suggesting that these channels do not contribute to the elevated [Ca2+]i. Conversely, inhibition of inositol trisphosphate receptors with xestospongin C produced a partial reduction in [Ca2+]i. These results demonstrate that an elevation in resting [Ca2+]i, contributed by aberrant Ca2+entry and release pathways, should be considered a major component of the abnormal Ca2+ homeostasis associated with AD.
Brain‐derived neurotrophic factor over‐expression in the forebrain ameliorates Huntington’s disease phenotypes in mice
Authors: Gharami Kusumika , Xie Yuxiang , An Juan Ji , Tonegawa Susumu , Xu Baoji 
Published: March 2008

AbstractHuntington’s disease (HD), a dominantly inherited neurodegenerative disorder characterized by relatively selective degeneration of striatal neurons, is caused by an expanded polyglutamine tract of the huntingtin (htt) protein. The htt mutation reduces levels of brain‐derived neurotrophic factor (BDNF) in the striatum, likely by inhibiting cortical BDNF gene expression and anterograde transport of BDNF from cortex to striatum. However, roles of the BDNF reduction in HD pathogenesis have not been established conclusively. We reasoned that increasing striatal BDNF through over‐expression would slow progression of the disease if BDNF reduction plays a pivotal role in HD pathogenesis. We employed a Bdnf transgene driven by the promoter for the alpha subunit of Ca2+/calmodulin‐dependent kinase II to over‐express BDNF in the forebrain of R6/1 mice which express a fragment of mutant htt with a 116‐glutamine tract. The Bdnf transgene increased BDNF levels and TrkB signaling activity in the striatum, ameliorated motor dysfunction, and reversed brain weight loss in R6/1 mice. Furthermore, it normalized DARPP‐32 expression of the 32 kDa dopamine and cAMP‐regulated phosphoprotein, increased the number of enkephalin‐containing boutons, and reduced formation of neuronal intranuclear inclusions in the striatum of R6/1 mice. These results demonstrate crucial roles of reduced striatal BDNF in HD pathogenesis and suggest potential therapeutic values of BDNF to HD.
SYNCRIP, a component of dendritically localized mRNPs, binds to the translation regulator BC200 RNA
Authors: Duning Kerstin , Buck Friedrich , Barnekow Angelika , Kremerskothen Joachim 
Published: March 2008

AbstractDendritic transport of (m)RNA molecules and localized translation at post‐synaptic sites is connected to synaptic plasticity and memory formation. Brain cytoplasmic RNA, 200nt (BC200 RNA) is a brain‐specific, small non‐messenger RNA with a somatodendritic distribution in primate neurons. The transcript is a component of a ribonucleoprotein particle that is thought to act as a regulator of decentralized translation in dendrites. To elucidate the cellular function of the BC200 ribonucleoprotein particle, we purified BC200 RNA‐binding proteins from human brain. Here, we describe the interaction of human Synaptotagmin‐binding cytoplasmic RNA interacting protein (SYNCRIP) with BC200 RNA. SYNCRIP was recently characterized as a component of large mRNA transport granules in neurons and is probably involved in local protein synthesis at post‐synaptic sites. Our in vitro binding studies demonstrate that SYNCRIP interacts specifically with BC200 RNA and that binding is mediated through its N‐terminal RNA recognition motifs and the internal A‐rich region of BC200 RNA, respectively. Furthermore, immunoprecipitation experiments indicate an in vivo association of SYNCRIP and BC200 RNA in human brain. Thus, SYNCRIP may recruit BC200 RNA into mRNA transport complexes involved in the regulation of localized translation in dendrites.
Modulation of dopaminergic neurotransmission in rat striatum uponin vitroandin vivodiclofenac treatment1
Authors: Milusheva Elisaveta , Baranyi Mária , Kittel Agnes , Fekete Adam , Zelles Tibor , Vizi E. Sylvester , Sperlágh Beáta 
Published: March 2008

AbstractDiclofenac (DCF) is a widely used non‐steroidal anti‐inflammatory drug, which also act as a mitochondrial toxin. As it is known that selective mitochondrial complex I inhibition combined with mild oxidative stress causes striatal dopaminergic dysfunction, we tested whether DCF also compromise dopaminergic function in the striatum. [3H]Dopamine ([3H]DA) release was measured from rat striatal slices afterin vitro(2 h, 10–25 μmol/L) orin vivo(3 mg/kg i.v. for 28 days) DCF treatment.In vitrotreatment significantly decreased [3H]DA uptake and dopamine (DA) content of the slices. H2O2(0.1 mmol/L)‐evoked DA release was enhanced. Intracellular reactive oxygen species production was not significantly changed in the presence of DCF. Afterin vivoDCF treatment no apparent decrease in striatal DA content was observed and the uptake of [3H]DA into slices was increased. The intensity of tyrosine hydroxylase immunoreactivity in the striatum was highly variable, and both decrease and increase were observed in individual rats. The H2O2‐evoked [3H]DA release was significantly decreased and the effluent contained a significant amount of [3H]octopamine, [3H]tyramine, and [3H]β‐phenylethylamine. The ATP content and adenylate energy charge were decreased. In conclusion, whereasin vitroDCF pre‐treatment resembles the effect of the mitochondrial toxin rotenone,in vivoit rather counteracts than aggravates dopaminergic dysfunction.
Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction
Authors: Nafia Imane , Re Diane B. , Masmejean Frédérique , Melon Christophe , Kachidian Philippe , Kerkerian‐Le Goff Lydia , Nieoullon André , Had‐Aissouni Laurence 
Published: March 2008

AbstractNigral depletion of the main brain antioxidant GSH is the earliest biochemical event involved in Parkinson’s disease pathogenesis. Its causes are completely unknown but increasing number of evidence suggests that glutamate transporters [excitatory amino acid transporters (EAATs)] are the main route by which GSH precursors may enter the cell. In this study, we report that dopamine (DA) neurons, which express the excitatory amino acid carrier 1, are preferentially affected by EAAT dysfunction when compared with non‐DA neurons. In rat embryonic mesencephalic cultures, l‐trans‐pyrrolidine‐2,4‐dicarboxylate, a substrate inhibitor of EAATs, is directly and preferentially toxic for DA neurons by decreasing the availability of GSH precursors and lowering their resistance threshold to glutamate excitotoxicity through NMDA‐receptors. In adult rat, acute intranigral injection of l‐trans‐pyrrolidine‐2,4‐dicarboxylate induces a large regionally selective and dose‐dependent loss of DA neurons and α‐synuclein aggregate formation. These data highlight for the first time the importance of excitatory amino acid carrier 1 function for the maintenance of antioxidant defense in DA neurons and suggest its dysfunction as a candidate mechanism for the selective death of DA neurons such as occurring in Parkinson’s disease.
Cell type‐specific subunit composition of G protein‐gated potassium channels in the cerebellum
Authors: Aguado Carolina , Colón José , Ciruela Francisco , Schlaudraff Falk , Cabañero Maria José , Perry Cydne , Watanabe Masahiko , Liss Birgit , Wickman Kevin , Luján Rafael 
Published: March 2008

AbstractG protein‐gated inwardly rectifying potassium (GIRK/Kir3) channels regulate cellular excitability and neurotransmission. In this study, we used biochemical and morphological techniques to analyze the cellular and subcellular distributions of GIRK channel subunits, as well as their interactions, in the mouse cerebellum. We found that GIRK1, GIRK2, and GIRK3 subunits co‐precipitated with one another in the cerebellum and that GIRK subunit ablation was correlated with reduced expression levels of residual subunits. Using quantitative RT‐PCR and immunohistochemical approaches, we found that GIRK subunits exhibit overlapping but distinct expression patterns in various cerebellar neuron subtypes. GIRK1 and GIRK2 exhibited the most widespread and robust labeling in the cerebellum, with labeling particularly prominent in granule cells. A high degree of molecular diversity in the cerebellar GIRK channel repertoire is suggested by labeling seen in less abundant neuron populations, including Purkinje neurons (GIRK1/GIRK2/GIRK3), basket cells (GIRK1/GIRK3), Golgi cells (GIRK2/GIRK4), stellate cells (GIRK3), and unipolar brush cells (GIRK2/GIRK3). Double‐labeling immunofluorescence and electron microscopies showed that GIRK subunits were mainly found at post‐synaptic sites. Altogether, our data support the existence of rich GIRK molecular and cellular diversity, and provide a necessary framework for functional studies aimed at delineating the contribution of GIRK channels to synaptic inhibition in the cerebellum.
Trans‐4‐hydroxy‐2‐hexenal is a neurotoxic product of docosahexaenoic (22:6; n‐3) acid oxidation
Authors: Long Eric K. , Murphy Tonya C. , Leiphon Laura J. , Watt John , Morrow Jason D. , Milne Ginger L. , Howard Jocelyn R. H. , Picklo Matthew J. 
Published: March 2008

AbstractLipid peroxidation of docosahexaenoic (22:6; n‐3) acid (DHA) is elevated in the CNS in patients with Alzheimer’s disease and in animal models of seizure and ethanol withdrawal. One product of DHA oxidation is trans‐4‐hydroxy‐2‐hexenal (HHE), a six carbon analog of the n‐6 fatty acid derived trans‐4‐hydroxy‐2‐nonenal (HNE). In this work, we studied the neurotoxic potential of HHE. HHE and HNE were toxic to primary cultures of cerebral cortical neurons with LD50’s of 23 and 18 μmol/L, respectively. Toxicity was prevented by the addition of thiol scavengers. HHE and HNE depleted neuronal GSH content identically with depletion observed with 10 μmol/L of either compound. Using an antibody raised against HHE–protein adducts, we show that HHE modified specific proteins of 75, 50, and 45 kDa in concentration‐ and time‐dependent manners. The time‐dependent formation of HHE differed from that of F4‐neuroprostanes following in vitro DHA oxidation likely as a result of the different oxidation pathways involved. Using purified mitochondrial aldehyde dehydrogenase ALDH5A, we found that HHE was oxidized 6.5‐fold less efficiently than HNE. Our data demonstrate that HHE and HNE have similarities but also differences in their neurotoxic mechanisms and metabolism.
Cytoskeletal protein carbonylation and degradation in experimental autoimmune encephalomyelitis
Authors: Smerjac Suzanne M. , Bizzozero Oscar A. 
Published: March 2008

AbstractProtein carbonylation, the non‐enzymatic addition of aldehydes or ketones to specific amino acid residues, has been implicated in the pathophysiology of multiple sclerosis. In this study, we investigated whether protein carbonyls also accumulate in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE). Western blots analysis after derivatization with dinitrophenyl hydrazine (oxyblot) showed elevated protein carbonylation at the time of maximal clinical disability. During the same period glutathione levels were substantially reduced, suggesting a causal relationship between these two markers. In contrast, lipid peroxidation products accumulated in EAE spinal cord well before the appearance of neurological symptoms. Carbonyl staining was not restricted to inflammatory lesions but present throughout the spinal cord particularly in neuronal cell bodies and axons. By 2‐dimensional‐oxyblot, we identified several cytoskeletal proteins, including β‐actin, glial acidic fibrillary protein, and the neurofilament proteins as the major targets of carbonylation. These findings were confirmed by pull‐down experiments, which also showed an increase in the number of carbonylated β‐actin molecules and a decrease in that of oxidized neurofilament proteins in EAE. These data suggest the possibility that oxidation targets neurofilament proteins for degradation, which may contribute to axonal pathology observed in multiple sclerosis and EAE.
Serum‐ and glucocorticoid‐inducible kinase 1 enhances zif268 expression through the mediation of SRF and CREB1 associated with spatial memory formation
Authors: Tyan Shiaw‐Wei , Tsai Ming‐Chi , Lin Chien‐Ling , Ma Yun‐Li , Lee Eminy H. Y. 
Published: March 2008

AbstractSerum‐ and glucocorticoid‐inducible kinase 1 (SGK1) has been shown to play an important role in spatial memory formation, but the molecular mechanism underlying this effect of SGK1 was not known. zif268 is an immediate early gene that is induced by water maze learning. To investigate the role of SGK1 in the regulation of zif268 expression, the dominant negative mutant of SGK1, SGK1 S422A, was infused to the hippocampal CA1 area of rats, and was found to decrease significantly the mRNA level of zif268 in both naïve animals and trained animals. SGK1 was also found to phosphorylate serum response factor (SRF) at Ser73, Ser75, and Ser99, and phosphorylate CREB1 at Ser133. Inhibition of SGK1 phosphorylation sites on SRF and CREB1 with alanine substitution significantly diminished SGK1‐enhanced zif268 expression in the promoter‐luciferase assay. SGK1 also phosphorylates Elk‐1 and SGK1 phosphorylation of Elk‐1 decreased the transcriptional activity of Elk‐1. But SGK1 phosphorylation of Elk‐1 did not affect SGK1‐enhanced zif268 expression. Moreover, the phosphorylation of SGK1 was increased in rat CA1 area after water maze learning, accompanied by increased phosphorylation of SRF at Ser99 and increased phosphorylation of CREB1 at Ser133. All these effects were antagonized by SGK1 S422A transfection. These results together suggest that SGK1 enhances zif268 expression through the mediation of SRF and CREB1, and these signaling pathways are associated with spatial memory formation in rats.
Gabapentin produces PKA‐dependent pre‐synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice
Authors: Takasu Keiko , Ono Hideki , Tanabe Mitsuo 
Published: March 2008

AbstractWe have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to ameliorate pain hypersensitivity in mice with partial nerve ligation. To clarify the supraspinal mechanism of action of gabapentin, whole‐cell patch‐clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham‐operation, and the effects of gabapentin in the modulation of synaptic transmission were studied. Bath application of gabapentin (10, 30 and 100 μM) in a concentration‐dependent manner reduced the GABAAreceptor‐mediated inhibitory post‐synaptic currents (IPSCs) in slices prepared from partially nerve‐ligated mice, whereas glutamate‐mediated excitatory post‐synaptic currents were hardly affected. By contrast, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Although gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired‐pulse ratio, suggesting that gabapentin acts on the pre‐synaptic GABAergic nerve terminals in the LC. As the protein kinase A (PKA) inhibitor H‐89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, PKA‐mediated phosphorylation seems to be important for supraspinal gabapentin responsiveness in neuropathic conditions. Together, gabapentin generates PKA‐dependent pre‐synaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons only under neuropathic pain states. These findings provide crucial evidence of how supraspinally acting gabapentin recruits the descending noradrenergic system.
The Akt signaling pathway contributes to postconditioning’s protection against stroke; the protection is associated with the MAPK and PKC pathways
Authors: Gao Xuwen , Zhang Hanfeng , Takahashi Tetsuya , Hsieh Jason , Liao Janette , Steinberg Gary K. , Zhao Heng 
Published: March 2008

AbstractWe previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long‐term protection and exploring underlying mechanisms involving the Akt, mitogen‐activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post‐conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3‐kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated‐phosphatase and tensin homologue deleted on chromosome 10 or ‐phosphoinositide‐dependent protein kinase‐1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated‐glycogen synthase kinase 3β, an Akt effector. In addition, postconditioning blocked β‐catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non‐phosphorylated active β‐catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated‐c‐Jun N‐terminal kinase and extracellular signal‐regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death‐promoting δPKC cleavage and attenuated reduction in phosphorylation of survival‐promoting εPKC. In conclusion, our data suggest that postconditioning provides long‐term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning’s protection; furthermore, increases in εPKC activity, a survival‐promoting pathway, and reductions in MAPK and δPKC activity; two putative death‐promoting pathways correlate with postconditioning’s protection.
The TRPV1 receptor is associated with preferential stress in large dorsal root ganglion neurons in early diabetic sensory neuropathy
Authors: Hong Shuangsong , Agresta Laura , Guo Chunfang , Wiley John W. 
Published: March 2008

AbstractChronic diabetic neuropathy is associated with peripheral demyelination and degeneration of nerve fibers. The mechanism(s) underlying neuronal injury in diabetic sensory neuropathy remain poorly understood. Recently, we reported increased expression and function of transient receptor potential vanilloid 1 (TRPV1) in large dorsal root ganglion (DRG) neurons in diabetic sensory neuropathy. In this study, we examined the effects of TRPV1 activation on cell injury pathways in this subpopulation of neurons in the streptozotocin‐induced diabetic rat model. Large DRG neurons from diabetic (6–8 weeks) rats displayed increased oxidative stress and activation of cell injury markers compared with healthy controls. Capsaicin (CAP) treatment induced decreased labeling of MitoTracker Red and increased cytosolic cytochrome c and activation of caspase 3 in large neurons isolated from diabetic rats. CAP treatment also induced oxidative stress in large diabetic DRG neurons, which was blocked by pre‐treatment with caspase or calpain inhibitor. In addition, both μ‐calpain expression and calpain activity were significantly increased in DRG neurons from diabetic rats after CAP treatment. Treatment with capsazepine, a competitive TRPV1 antagonist, markedly reduced these abnormalities in vitro and prevented activation of cell injury in large DRG neurons in diabetic rats in vivo. These results suggest that activation of the TRPV1 receptor activates pathways associated with caspase‐dependent and calpain‐dependent stress in large DRG neurons in STZ‐diabetic rats. Activation of the TRPV1 receptor may contribute to preferential neuronal stress in large DRG neurons relatively early in diabetic sensory neuropathy.
Helicobacter pylori and Antrum Erosion‐Specific Gene Expression Patterns: The Discriminative Role of CXCL13 and VCAM1 Transcripts
Authors: Galamb Orsolya , Gyõrffy Balázs , Sipos Ferenc , Dinya Elek , Krenács Tibor , Berczi Lajos , Szõke Dominika , Spisák Sándor , Solymosi Norbert , Németh Anna Mária , Juhász Márk , Molnár Béla , Tulassay Zsolt 
Published: March 2008

AbstractBackground and Aims:  Chronic Helicobacter pylori infection affects approximately half of the world, leads to chronic gastritis and peptic ulceration, and is linked to gastric carcinoma. Our aims were to compare the gene expression profile (GEP) of H. pylori‐positive and H. pylori‐negative gastric erosions and adjacent mucosa to explain the possible role and response to H. pylori infection and to get erosion‐related mRNA expression patterns.Methods:  Total RNA was extracted, amplified, and biotinylated from gastric biopsies of patients with H. pylori‐positive and H. pylori‐negative antrum erosions (ER) (8/8) and adjacent macroscopically normal mucosae (8/8). The GEP was evaluated using HGU133plus2.0 microarrays. Two independent normalizations (MAS5.0, RMA), PAM feature selection, hierarchical cluster analysis, and discriminant analysis were done. The expression of 14 genes was also measured by real‐time‐polymerase chain reaction. VCAM‐1 and CXCL13 immunohistochemistry (IHC) was done.Results:  In H. pylori infection, significant overexpression of MHC class II antigen‐presenting genes, interleukin‐7 receptor, ubiquitin‐D, CXCR4, lactoferrin immune response‐related genes, CXCL‐2 and ‐13, CCL18 chemokine ligand, and VCAM‐1 genes were established. In erosive gastritis, increased proliferation (MET) and transport (UCP2, SCFD1, KPNA4) were found, while genes associated with adhesion (SIGLEC11), transcription regulation (ESRRG), and electron and ion transport (ACADM, CLIC6) were down‐regulated. Discriminant analysis successfully classified all samples into four groups (HP+ER–, HP+ER+, HP–ER+, HP–ER–) using a reduced gene set (20). Significant overexpression of VCAM‐1 and CXC13 protein was detected by IHC in HP+ samples (p < .05).Conclusions:  Whole genomic microarray analysis yielded new H. pylori infection and erosion‐related gene expression changes. Discriminative genes can be used in mRNA‐based diagnostic classification of gastric biopsies.