bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocyte metabolism is disturbed in the early development of experimental hydrocephalus
Authors: Kondziella Daniel , Qu Hong , Lüdemann Wolf , Brinker Thomas , Sletvold Olav , Sonnewald Ursula 
Published: July 2010

AbstractThe proper diagnosis of the arrested or the progressive form of hydrocephalus has a critical impact on treatment, but remains difficult. The assessment of early changes in cerebral metabolism might help in the development of adequate non‐invasive diagnostic tools. This study examined the alterations in label incorporation in neurotransmitter amino acids and other compounds in kaolin‐induced progressive hydrocephalus in rats by means of magnetic resonance spectroscopy (MRS) combined with the administration of [1‐13C]glucose and [1,2‐13C]acetate. Some 2, 4 and 6 weeks after kaolin injection into the cisterna magna, cerebrum, brainstem and cerebellum were dissected. Interestingly, labelling of most amino acids derived from [1‐13C]glucose showed no alterations, whereas labelling from [1,2‐13C]acetate was affected. Two weeks after induction of hydrocephalus the taurine concentration was decreased, whereas the concentration of [1,2‐13C]lactate was increased in the cerebrum and that of [1,2‐13C]GABA in the brainstem. Furthermore, labelling from [1,2‐13C]acetate was significantly decreased in [4,5‐13C]glutamate, [1,2‐13C]glutamate and [1,2‐13C]GABA in cerebrum from 4 weeks after hydrocephalus induction. The concentration ofN‐acetylaspartate, a neuronal marker, was unchanged. However, labelling of the acetyl group from [1‐13C]glucose was decreased in cerebellum and brainstem at 6 weeks after the induction of hydrocephalus. As glucose is metabolized predominately by neurones, whereas acetate is exclusively taken up by astrocytes, these results indicate that mostly astrocytic, and only later neuronal, metabolism is disturbed in the kaolin model of hydrocephalus. If verified in patients usingin vivoMRS, impaired astrocyte metabolism might serve as an early indication for operative treatment.
Early events of target deprivation/axotomy‐induced neuronal apoptosis in vivo: oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins
Authors: Martin Lee J. , Price Anne C. , McClendon Karen B. , Al‐Abdulla Nael A. , Subramaniam Jamuna R. , Wong Philip C. , Liu Zhiping 
Published: July 2010

AbstractThe mechanisms of injury‐ and disease‐associated apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex induces apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN), by 7 days post‐lesion, that is p53 modulated and Bax dependent. We tested the hypothesis that this degenerative process is initiated by oxidative stress and early formation of DNA damage and is accompanied by changes in the levels of pro‐apoptotic mediators of cell death. Immunoblotting revealed that the protein profiles of Bax, Bak and Bad were different during the progression of neuronal apoptosis in the LGN. Bax underwent a subcellular redistribution by 1 day post‐lesion, while Bak increased later. Bad showed an early sustained increase. Cleaved caspase‐3 was elevated maximally at 5 and 6 days. Active caspase‐3 underwent a subcellular translocation to the nucleus. A dramatic phosphorylation of p53 was detected at 4 days post‐lesion. DNA damage was assessed immunocytochemically as hydroxyl radical adducts (8‐hydroxy‐2‐deoxyguanosine) and single‐stranded DNA. Both forms of DNA damage accumulated early in target‐deprived LGN neurons. Transgenic overexpression of superoxide dismutase‐1 provided significant protection against the apoptosis but antioxidant pharmacotreatments with trolox and ascorbate were ineffective. We conclude that overlapping and sequential signaling pathways are involved in the apoptosis of adult brain neurons and that DNA damage generated by superoxide derivatives is an upstream mechanism for p53‐regulated, Bax‐dependent apoptosis of target‐deprived neurons.
Orphan nuclear receptor Nurr1 directly transactivates the promoter activity of the tyrosine hydroxylase gene in a cell‐specific manner
Authors: Kim Kwang‐Soo , Kim Chun‐Hyung , Hwang Dong‐Youn , Seo Hyemyung , Chung Sangmi , Hong Seok Jong , Lim Jin‐Kyu , Anderson Therese , Isacson Ole 
Published: July 2010

AbstractTyrosine hydroxylase (TH) catalyzes the first and rate‐limiting step of catecholamine synthesis and its expression is necessary for neurotransmitter specification of all catecholaminergic neurons, while dopamine β‐hydroxylase (DBH) is essential for the noradrenergic phenotype. In the present study, we show that Nurr1, an orphan nuclear receptor critical for dopaminergic (DA) neuron development, directly transactivates the promoter activity of the TH gene in a cell type‐dependent manner, while it does not regulate the DBH promoter. Consistent with these results, only the TH promoter contains multiple sequence motifs homologous to the known Nurr1‐binding motif, NBRE. TH promoter deletional analysis indicates that < 1.0 kb upstream sequences, encompassing three NBRE‐like motifs (i.e. NL1, NL2 and NL3) are mostly responsible for the effects of Nurr1. Among these potential motifs, site‐directed mutational analysis showed that NL1, residing from − 35 to − 28 bp, was most critical for mediating the transactivation by Nurr1. Strikingly, however, both DNase I footprinting and electrophoretic mobility shift assays showed that NL3, but not NL1 or NL2, has high binding affinity to Nurr1. To determine whether the proximity of these motifs may be important for transactivation by Nurr1 in the transient transfection assay, we generated reporter gene constructs in which NL3 is immediately proximal to the TATA box. Indeed, NL3 was more efficient in this position than NL1 or NL2 for mediating the transactivation by Nurr1. Our results suggest that Nurr1 may play a direct role for specification of DA neurotransmitter identity by activating TH gene transcription in a cell context‐dependent manner.
Ero1‐L, an ischemia‐inducible gene from rat brain with homology to global ischemia‐induced gene 11 (Giig11), is localized to neuronal dendrites by a dispersed identifier (ID) element‐dependent mechanism
Authors: Chen Dexi , Jin Kunlin , Kawaguchi Kenji , Nakayama Masaki , Zhou Xiaoman , Xiong Zhigang , Zhou An , Mao Xiao Ou , Greenberg David A. , Graham Steven H. , Simon Roger P. 
Published: July 2010

AbstractMany changes in neuronal gene expression occur in response to ischemia, and these may play a role in determining the fate of ischemic neurons. To identify genes induced in the rat brain following cerebral ischemia, a strategy was used that combines subtractive hybridization and differential screening. Among the genes identified was one referred to as global ischemia‐inducible gene 11(Giig11). Sequence analysis indicated that Giig11 exhibited 97% and 91% identity to the known Ero1‐L (S. cereviseae ero1‐like oxidoreductase) of mouse and human origin, which is involved in oxidative endoplasmic reticulum protein folding. Rat Ero1‐L/Giig11 also contains a l07‐bp sequence that is nearly identical (> 95%) to the known dispersed repetitive identifier (ID), but which is lacking in mouse and human Ero1‐L. Northern blotting showed that expression of the ID element and Ero1‐L/Giig11 mRNA increased after global cerebral ischemia. In situ hybridization demonstrated increased expression of Ero1‐L/Giig11 in the brain following ischemic injury, with the highest levels in the vulnerable hippocampal CA1 pyramidal neurons. Transfection of cultured primary hippocampal neurons with a plasmid containing green fluorescent protein (gfp) and Ero1‐L/Giig11 cDNA (with and without the ID element) produced a gfp‐Ero1‐L/Giig11 fusion protein, and more fusion protein was localized into dendrites in the presence of the ID element, suggesting that the ID element promotes Ero1‐L/Giig11 protein localization to dendrites. Therefore, Ero‐1L/Giig11 may have a role in ischemia‐induced neuronal repair or survival mechanisms directed at counteracting abnormalities in protein folding, maturation and distribution.
Adenosine A2Areceptor‐mediated facilitation of noradrenaline release involves protein kinase C activation and attenuation of presynaptic inhibitory receptor‐mediated effects in the rat vas deferens
Authors: Queiroz Glória , Talaia Carlos , Gonçalves Jorge 
Published: July 2010

AbstractIn the epididymal portion of rat vas deferens, facilitation of noradrenaline release mediated by adenosine A2Areceptors, but not that mediated by β2‐adrenoceptors or by direct activation of adenylyl cyclase, was attenuated by blockade of α2‐adrenoceptors and abolished by simultaneous blockade of α2‐adrenoceptors, adenosine A1and P2Y receptors. The adenosine A2Areceptor‐mediated facilitation was not changed by inhibitors of protein kinase A, protein kinase G or calmodulin kinase II but was prevented by inhibition of protein kinase C with chelerythrine or bisindolylmaleimide XI. Activation of protein kinase C with phorbol 12‐myristate 13‐acetate caused a facilitation of noradrenaline release that was abolished by bisindolylmaleimide XI and reduced by antagonists of α2‐adrenoceptors, adenosine A1and P2Y receptors. Activation of adenosine A2Areceptors attenuated the inhibition of noradrenaline release mediated by the presynaptic inhibitory receptors. This effect was mimicked by phorbol 12‐myristate 13‐acetate and prevented by bisindolylmaleimide XI. It is concluded that adenosine A2Areceptors facilitate noradrenaline release by a mechanism that involves a protein kinase C‐mediated attenuation of effects mediated by presynaptic inhibitory receptors, namely α2‐adrenoceptors, adenosine A1and P2Y receptors.
Squid visual arrestin: cDNA cloning and calcium‐dependent phosphorylation by rhodopsin kinase (SQRK)
Authors: Mayeenuddin Linnia H. , Mitchell Jane 
Published: July 2010

AbstractArrestin binding to rhodopsin is one of the major mechanisms of termination of photoresponses in both vertebrates and invertebrates. Here we report the cDNA cloning and characterization of a 48‐kDa visual arrestin from squid (Loligo pealei). The cDNA encoded a protein that had 56–64% amino acid sequence similarity to reported arrestin sequences. This protein does not encode any distinct modular domains but contains five fingerprint regions that have been identified within arrestins. Antibodies raised to the recombinant arrestin protein detected arrestin expression only in the eye and recognized a doublet in photoreceptor membranes, representing unphosphorylated and phosphorylated arrestin. In squid eye membranes, arrestin was phosphorylated in a Ca2+‐dependent manner and this phosphorylation was inhibited by antibodies raised against squid rhodopsin kinase, but not by inhibitors of protein kinase C or calmodulin kinase. Addition of purified squid rhodopsin kinase to washed rhabdomeric membranes resulted in phosphorylation of rhodopsin, and arrestin was also phosphorylated when calcium was present. This is the first report of a rhodopsin kinase phosphorylating an arrestin substrate, and suggests a dual role for this kinase in the inactivation of the squid visual system.
Hypoxia induces de‐stabilization of the LAT1 large neutral amino acid transporter mRNA in brain capillary endothelial cells
Authors: Boado Ruben J. , Li Jian Yi , Tsukamoto Haruhisa , Pardridge William M. 
Published: July 2010

AbstractBlood–brain barrier (BBB) transport of large neutral amino acids is mediated by the large neutral amino acid transporter type 1 (LAT1 transporter). Although the gene encoding the Glut1 glucose transporter is up‐regulated in hypoxia, the response of the LAT1 gene to hypoxia is not known. The present study investigates the changes in the LAT1 mRNA in cultured bovine brain capillary endothelial cells exposed to 1% O2 for 24–48 h. The LAT1 mRNA was initially down‐regulated in hypoxia with reciprocal changes in the Glut1 mRNA. No changes in the 4F2hc mRNA in hypoxia were observed. Hypoxia caused an initial de‐stabilization of the LAT1 mRNA, and the t1/2 of the LAT1 mRNA in control and hypoxic cells was 6.4 ± 0.5 and 2.4 ± 0.1 h, respectively. To further explore post‐transcriptional regulation of LAT1 gene expression, the polysome and cytosol fractions of the control and hypoxic endothelial cells were isolated, and LAT1 mRNA binding proteins were detected by ultraviolet light cross‐linking. Whereas the cytosol contained no LAT1 mRNA binding proteins, the cell polysome fraction expressed several LAT1 mRNA binding proteins, including principal 40‐, 70‐ and 80‐kDa proteins. These studies are consistent with post‐transcriptional de‐stabilization of the LAT1 large neutral amino acid transporter in hypoxia.
Antipsychotic drugs differentially modulate apolipoprotein D in rat brain
Authors: Khan M. M. , Parikh V. V. , Mahadik S. P. 
Published: July 2010

AbstractApolipoprotein‐D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post‐mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, haloperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate‐putamen (p = 0.027–0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL‐induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post‐treatment, either with RISP or OLZ, was very effective in restoring the HAL‐induced reduction of apoD, as well as cellular morphology. Similarly, pre‐treatments were also effective, but slightly less than post‐treatment, in preventing HAL‐induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra‐pyramidal symptoms in schizophrenia.
Conditions associated with ER dysfunction activate homer 1a expression
Authors: Paschen Wulf , Mengesdorf Thorsten 
Published: July 2010

SummaryHomer proteins physically link metabotropic glutamate receptors with IP3 receptors located at the endoplasmic reticulum (ER) and thereby modulate receptor‐activated calcium signaling. Homer 1a, the short form of constitutively expressed homer 1 proteins, exerts dominant negative activity with respect to homer 1 proteins by interfering with the formation of multiprotein complexes. Homer 1a is an immediate early gene, the expression of which is activated by various stimuli including glutamate receptor activation. The mechanisms underlying activation of homer 1a expression are however, not fully understood. Here, we show that homer 1a expression is induced in neuronal cell cultures under experimental conditions associated with ER dysfunction. Increased homer 1a mRNA levels were found in 2 sets of cultures: in those exposed to thapsigargin, a specific inhibitor of ER Ca2+‐ATPase, after a transient depletion of ER calcium stores through exposure to calcium‐free medium supplemented with EGTA, and in those exposed to a proteasome inhibitor known to induce ER dysfunction. Thus, homer 1a expression may be activated by impairment of ER functioning just as it is by glutamate receptor activation.
Neuronal‐NOS adaptor protein expression after spreading depression: implications for NO production and ischemic tolerance
Authors: Wiggins Amanda K. , Shen Pei‐Juan , Gundlach Andrew L. 
Published: July 2010

AbstractCortical spreading depression (CSD) is characterized by slowly propagating waves of neuronal/astrocytic depolarization and metabolic changes, followed by a period of quiescent neuronal and electroencephalographic activity. CSD acts as a preconditioning stimulus in brain, reducing cell death when elicited up to several days prior to an ischemic insult. Precise mechanisms associated with this neuroprotection are not known, although CSD increases the expression of a number of potentially neuroprotective genes/proteins. The nitric oxide (NO) system may be of particular importance, as it is acutely activated and chronically up‐regulated in cerebral cortex by CSD, and NO can ameliorate and exacerbate cell death under different conditions. Several molecules have recently been identified that modulate the production and/or cellular actions of NO, but it is not known whether their expression is altered by CSD. Therefore, the present study examined the effect of CSD on the spatiotemporal expression of PIN, CAPON, PSD‐95, Mn‐SOD and Cu/Zn‐SOD mRNA in the rat brain. In situ hybridization using specific [35S]‐labelled oligonucleotides revealed that levels of PIN mRNA were significantly increased in the cortex and claustrum (∼30–180%; p ≤ 0.01) after 6 h and 1 and 2 days, but were again equivalent to contralateral (control) cortical values at 7, 14 and 28 days. CAPON mRNA levels were increased (∼30–180%; p ≤ 0.05) in the ipsilateral cortical hemisphere at 6 h and 2 days post treatment, but not at the other times examined. In contrast, levels of PSD‐95, Mn‐ and Cu/Zn‐SOD mRNA were not altered at any time after CSD. These results suggest that following CSD, nNOS activity and NO levels may be tightly regulated by both transcriptional and translational alterations in a range of nNOS adaptor proteins, which may contribute to CSD‐induced neuroprotection against subsequent ischemia.
RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia
Authors: Dracheva Stella , Elhakem Sharif L. , Marcus Sue M. , Siever Larry J. , McGurk Susan R. , Haroutunian Vahram 
Published: July 2010

AbstractSerotonin 2C receptor (5‐HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5‐HT2CR mRNA undergoes adenosine‐to‐inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5‐HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5‐HT2CR‐tr) which encodes a non‐functional serotonin receptor. 5‐HT2CR mRNA editing efficiencies and the expression of the full‐length and the truncated 5‐HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5‐HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5‐HT2CR and 5‐HT2CR‐tr mRNA variants revealed that the expression of 5‐HT2CR‐tr was ∼ 50% of that observed for the full‐length isoform.
Inducible cAMP early repressor (ICER) in the nervous system – a transcriptional regulator of neuronal plasticity and programmed cell death
Authors: Mioduszewska Barbara , Jaworski Jacek , Kaczmarek Leszek 
Published: July 2010

AbstractThe acronym ICER (inducible cAMP early repressor) refers to a group of four proteins produced from the CREM/ICER gene due to use of an internal promoter (P2) placed in an intron of the CREM (cAMP responsive element modulator) gene. The ICER proteins contain DNA binding/leucine zipper domains that make them endogenous inhibitors of transcription driven by CREB (cAMP responsive element binding protein) and its cognates, CREM and ATF‐1 (activating transcription factor‐1). ICER expression is inducible in the brain and in neuronal culture by a variety of stimuli. As a CREB antagonist, ICER appears to be of pivotal importance in neuronal plasticity and programmed cell death.
Cyclin‐dependent kinase 11p110 and casein kinase 2 (CK2) inhibit the interaction between tyrosine hydroxylase and 14‐3‐3
Authors: Sachs Nancy A. , Vaillancourt Richard R. 
Published: July 2010

AbstractTyrosine hydroxylase (TH) is regulated by the reversible phosphorylation of serines 8, 19, 31 and 40. Upon initiation of this study, serine 19 was unique due to its requirement of 14‐3‐3 binding after phosphorylation for optimal enzyme activity, although it has been more recently demonstrated that phosphorylated serine 40 also binds 14‐3‐3. To identify proteins that interact with TH following phosphorylation of serine 19, this amino acid was mutated to alanine and THS19A was used as bait in a yeast two‐hybrid system. From this, mouse‐derived cyclin‐dependent kinase 11 (CDK11)p110 was identified as an interacting partner with THS19A. The interaction was confirmed using human CDK11p110 cDNA in a mammalian system. Previous research has demonstrated that casein kinase 2 (CK2) interacts with CDK11p110, and both were observed to phosphorylate TH in vitro. In addition, CDK11p110 overexpression was observed to inhibit the interaction between TH and 14‐3‐3. A mechanism contributing to disruption of the interaction between TH and 14‐3‐3 may be due to CK2 phosphorylation of specific 14‐3‐3 isoforms, i.e. 14‐3‐3 τ. Collectively, these results imply that CDK11p110 and CK2 negatively regulate TH catecholamine biosynthetic activity since phosphoserine 19 of TH requires 14‐3‐3 binding for optimal enzyme activity and a decreased rate of dephosphorylation.
Over‐expression of antioxidant enzymes protects cultured hippocampal and cortical neurons from necrotic insults
Authors: Wang Hui , Cheng Elise , Brooke Sheila , Chang Pearl , Sapolsky Robert 
Published: July 2010

AbstractThere is now considerable knowledge concerning neuron death following necrotic insults, and it is believed that the generation of reactive oxygen species (ROS) and oxidative damage play a pivotal role in the neuron death. Prompted by this, we have generated herpes simplex virus‐1 amplicon vectors over‐expressing the genes for the antioxidant enzymes catalase (CAT) or glutathione peroxidase (GPX), both of which catalyze the degradation of hydrogen peroxide. Over‐expression of each of these genes in primary hippocampal or cortical cultures resulted in increased enzymatic activity of the cognate protein. Moreover, each enzyme potently decreased the neurotoxicity induced by kainic acid, glutamate, sodium cyanide and oxygen/glucose deprivation. Finally, these protective effects were accompanied by parallel decreases in hydrogen peroxide accumulation and the extent of lipid peroxidation. These studies not only underline the key role played by ROS in the neurotoxicity of necrotic insults, but also suggest potential gene therapy approaches.