bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein associated with Myc (PAM) is involved in spinal nociceptive processing
Authors: Ehnert Corina , Tegeder Irmgard , Pierre Sandra , Birod Kerstin , Nguyen Hong‐Van , Schmidtko Achim , Geisslinger Gerd , Scholich Klaus 
Published: July 2010

AbstractPAM (protein associated with Myc) is a potent inhibitor of adenylyl cyclases (ACs) which is primarily expressed in neurones. Here we describe that PAM is highly expressed in dorsal horn neurones and motoneuron of the spinal cord, as well as in neurones of dorsal root ganglia in adult rats. PAM mRNA expression is differentially regulated during development in both spinal cord and dorsal root ganglia of rats, being strongest during the major respective synaptogenic periods. In adult rats, PAM expression was up‐regulated in the spinal cord after peripheral nociceptive stimulation using zymosan and formalin injection, suggesting a role for PAM in spinal nociceptive processing. Since PAM inhibited Gαs‐stimulated AC activity in dorsal root ganglia as well as spinal cord lysates, we hypothesized that PAM may reduce spinal nociceptive processing by inhibition of cAMP‐dependent signalling. Accordingly, intrathecal treatment with antisense but not sense oligonucleotides against PAM increased basal and Gαs‐stimulated AC activity in the spinal cord and enhanced formalin‐induced nociceptive behaviour in adult rats. Taken together our findings demonstrate that PAM is involved in spinal nociceptive processing.
Overexpression of torsinA in PC12 cells protects against toxicity
Authors: Shashidharan P. , Paris Nicolae , Sandu Daniela , Karthikeyan Laina , McNaught Kevin St P. , Walker Ruth H. , Olanow C. Warren 
Published: July 2010

AbstractChildhood‐onset dystonia is an autosomal dominant movement disorder associated with a three base pair (GAG) deletion mutation in the DYT1 gene. This gene encodes a novel ATP‐binding protein called torsinA, which in the central nervous system is expressed exclusively in neurons. Neither the function of torsinA nor its role in the pathophysiology of DYT1 dystonia is known. In order to better understand the cellular functions of torsinA, we established PC12 cell lines overexpressing wild‐type or mutant torsinA and subjected them to various conditions deleterious to cell survival. Treatment of control PC12 cells with an inhibitor of proteasomal activity, an oxidizing agent, or trophic withdrawal, resulted in cell death, whereas PC12 cells that overexpressed torsinA were significantly protected against each of these treatments. Overexpression of mutant torsinA failed to protect cells against trophic withdrawal. These results suggest that torsinA may play a protective role in neurons against a variety of cellular insults.
Up‐regulation of glutamate concentration in the putamen and in the prefrontal cortex of asymptomatic SIVmac251‐infected macaques without major brain involvement
Authors: Bossuet Christophe , Vaufrey Françoise , Condé Françoise , Chrétien Fabrice , Pichon Jacques , Hantraye Philippe , Le Grand Roger , Dormont Dominique , Gras Gabriel 
Published: July 2010

AbstractWe quantified putamen and prefrontal cortex metabolites in macaques with simian immunodeficiency virus infection and searched for virological and histological correlates. Fourteen asymptomatic macaques infected since 8–78 months (median: 38) were compared with eight uninfected ones. Absolute concentrations of acetate, alanine, aspartate, choline, creatine, GABA, glutamate, glutamine, lactate, myo‐inositol,N‐acetylaspartate, taurine and valine were determined byex vivoproton magnetic resonance spectroscopy. Glutamate concentration in the CSF was determined by HPLC. Gliosis was assessed by glial fibrillary acidic protein and CD68 immunohistochemistry. Glutamate concentration was slightly increased in the prefrontal cortex (19%,p = 0.0152,t‐test) and putamen (13%,p = 0.0354,t‐test) of the infected macaques, and was unaffected in the CSF. Myo‐inositol concentration was increased in the prefrontal cortex only (27%,p = 0.0136). The concentrations of glutamate and myo‐inositol in the prefrontal cortex were higher in the animals with marked or intense microgliosis (p = 0.0114). The other studied metabolites, includingN‐acetylaspartate, were not altered. Glutamate concentration may thus increase in the cerebral parenchyma in asymptomatic animals, but is not accompanied by a detectable decrease inN‐acetylaspartate concentration (neuronal dysfunction). Thus, there are probably compensatory mechanisms that may limit glutamate increase and/or counterbalance its effects.
Early anti‐inflammatory treatment reduces lipid peroxidation and protein nitration after spinal cord injury in rats
Authors: Bao Feng , Chen Yuhua , Dekaban Gregory A. , Weaver Lynne C. 
Published: July 2010

AbstractWe investigated mechanisms by which a monoclonal antibody (mAb) against the CD11d subunit of the leukocyte integrin CD11d/CD18 improves neurological recovery after spinal cord injury (SCI) in the rat. The effects of an anti‐CD11d mAb treatment were assessed on ED‐1 expression (estimating macrophage infiltration), myeloperoxidase activity (MPO, approximating neutrophil infiltration), lipid peroxidation, inducible nitric oxide synthase (iNOS) and nitrotyrosine (indicating protein nitration) expression in the spinal cord lesion after severe clip‐compression injury. Protein expression was evaluated by western blotting and immunocytochemistry. Lipid peroxidation was assessed by thiobarbituric acid reactive substances (TBARS) production. After anti‐CD11d mAb treatment, decreased ED‐1 expression at 6–72 h after SCI indicated reduced macrophage infiltration. MPO activity (units/g tissue) was reduced significantly from 114 ± 11 to 75 ± 8 (− 34%) at 6 h and from 38 ± 2 to 22 ± 4 (− 42%) at 72 h. After SCI, anti‐CD11d mAb treatment significantly reduced TBARS from 501 ± 61 to 296 ± 17 nm (− 41%) at 6 h and to approximately uninjured values (87 nm) at 72 h. The mAb treatment also attenuated the expression of iNOS and formation of nitrotyrosine at 6–72 h after SCI. These data indicate that anti‐CD11d mAb treatment blocks intraspinal neutrophil and macrophage infiltration, reducing the intraspinal concentrations of reactive oxygen and nitrogen species. These effects likely underlie improved tissue preservation and neurological function resulting from the mAb treatment.
Role of extracellular signal‐regulated kinase in the ventral tegmental area in the suppression of the morphine‐induced rewarding effect in mice with sciatic nerve ligation
Authors: Ozaki Satoru , Narita Minoru , Narita Michiko , Ozaki Masahiko , Khotib Junaidi , Suzuki Tsutomu 
Published: July 2010

AbstractWe recently reported that μ‐opioid receptor agonist morphine failed to induce its rewarding effects in rodents with sciatic nerve injury. In the present study, we investigated whether a state of neuropathic pain induced by sciatic nerve ligation could change the activities of the extracellular signal‐regulated kinase (ERK) and p38 in the mouse lower midbrain area including the ventral tegmental area (VTA), and these changes could directly affect the development of the morphine‐induced rewarding effect in mice. The sciatic nerve ligation caused a long‐lasting and profound thermal hyperalgesia. A dose‐dependent place preference induced by s.c. administration of morphine was observed in sham‐operated mice, but not in sciatic nerve‐ligated mice. We found here for the first time that nerve injury produces a sustained and significant reduction in protein levels of phosphorylated‐ERK and ‐p38 in cytosolic preparations of the mouse lower midbrain. The inhibition of ERK activity by i.c.v. pre‐treatment with either PD98059 or U0126 impaired the morphine‐induced place preference. In contrast, i.c.v. treatment with a specific inhibitor of p38, SB203580, did not interfere with the morphine‐induced rewarding effect. Immunohistochemical study showed a drastic reduction in phosphorylated‐ERK immunoreactivity within tyrosine hydroxylase‐positive cells of the VTA. These results suggest that a sustained reduction in the ERK‐dependent signalling pathway in dopamine cells of the VTA may be implicated in the suppression of the morphine‐induced rewarding effect under neuropathic pain.
Glutathione S‐transferase is a novel target for mood stabilizing drugs in primary cultured neurons
Authors: Wang Jun‐Feng , Shao Li , Sun Xiujun , Young L. Trevor 
Published: July 2010

AbstractOligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S‐transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose‐dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti‐oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium.
Aggregate formation and synaptic abnormality induced by DSCR1
Authors: Ma Hong , Xiong Hui , Liu Tong , Zhang Lingyan , Godzik Adam , Zhang Zhuohua 
Published: July 2010

AbstractAggregation of conformation‐abnormal peptides probably plays a key role in the pathogenesis of many neurodegenerative diseases. DSCR1 Down syndrome (DS) critical region 1, was identified from a chromosomal region (21q22.1‐q22.2) for the clinical manifestations of DS when an extra‐copy is present. We report that expression of DSCR1 in several cell types, including primary neurons, causes microtubule‐dependent aggresome‐like inclusion body formation. Disease‐associated huntingtin (Q148) and ataxin‐3 (Q84) co‐localize with DSCR1 aggregates. Neurons bearing DSCR1 aggregates show reduced synaptophysin staining in processes. DSCR1 residues 31–90 constitute an aggregation‐prone domain that is predicted to form a hydrophobic patch on the protein surface when residues 1–30 are removed. This study identifies a novel function of DSCR1 that may underlie DS neuropathology.
Neuroprotective properties of copper binding fragments of amyloid precursor protein and prion
Authors: Inestrosa N. C. , Chacon M. , Barria M. I. , Varela‐Nallar L. , Opazo C. 
Published: July 2010

We are particularly interested in the neurobiology of copper as a start point to understand the role of this metal on neurodevelopmental as well as in neurodegenerative processes. Here, we summarize our evidence that support a role in copper homeostasis of the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and the Prion protein (PrP), which is related to the Creutzfeldt–Jakob disease. First, APP and PrP possess copper reduction activity, measured by the bathocuproine assay, being cysteine and tryptophan key amino acids for oxidation (in APP and PrP, respectively). Second, PrP transcription is regulated by copper, both in primary neuronal cultures and in PC12 cell lines transfected with the PrP promoter. Finally, APP‐ and PrP‐copper binding domains rescue rats from copper induced neurotoxicity and spatial memory deficits induced by metal injection into the rat brain. Since APP and PrP proteins are localized at the plasma membrane, we proposed that their abilities to bind and reduce copper might play an important role as a primary neuronal response against copper neurotoxicity.Acknowledgements: Supported by FONDECYT No. 2990087 to C.O. and CIMM‐ICA, FONDAP‐Biomedicine No. 13980001, MIFAB and a Presidential Chair in Science (1999–2001) from the Chilean Government to N.C.I.
Selective neuronal vulnerability, protease‐activated receptors (PARS) and thrombin signalling
Authors: Festoff B. W. , Wu M. , Wong A. , Citron B. A. , Suo Z. 
Published: July 2010

In order to investigate the roles of thrombin and its signalling via PARs in defining selective neuronal vulnerability we compared two different murine clonal neuronal lines: NSC34 motor and HT22 hippocampal neurons. RT‐PCR revealed mRNA expression all four PARS. Responses of both cell lines for thrombin effects on neurite outgrowth, cell survival and signalling changes through mitogen activated protein kinases (MAPKs) were evaluated. Ability of thrombin and PAR‐specific active peptides (agonists): PAR1 (SFLLRN) and PAR4 (GYPGQV), were compared for these parameters and for the presence of aggregated microtubule‐associated protein (MAP) tau neurofibrillary tangles (NFTs). Motor neuronal PAR1 or PAR4 activation induced rapid neurite retraction and neuronal apoptosis. This was accompanied by tau degradation. In contrast, hippocampal neuronal PAR1 or PAR4 activation resulted in mild effects on neurite outgrowth but rapid tau aggregation, which was dependent on phosphorylation and positive for NFT‐specific antibody. Delayed reduction in cell viability occurred 24–48 h after tau aggregation. Evaluation of signalling pathways revealed p38 MAPK in NSC‐34 and p44/42 MAPK activation in HT22 cells were closely related to observed differential neuronal morphology in response to thrombin. We conclude that different intracellular signalling pathways coupled to PARs in different neuronal sub‐populations mediate selective thrombin vulnerability.Acknowledgements:  Supported by the DVA, Christopher Reeve Paralysis Foundation, Missouri Alzheimer's Res. Fund, ALS Association, Lied Endowment, KUMCRI and Midwest Biomedical Research Foundation.
NSAIDs protect dopaminergic neurons against 6‐OHDA and MPP+ toxicity
Authors: Werner P. , Carrasco E. 
Published: July 2010

Endogenous and environmental neurotoxins are among the suspected causes of the loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Non‐steroidal anti‐inflammatory drugs (NSAIDs) reduce inflammation by inhibiting cyclooxygenase (COX)‐dependent synthesis of prostaglandins (PG) from arachidonic acid. NSAIDs decrease the incidence of Alzheimer's disease, but little is known about their potential benefit for PD. Therefore, we examined whether NSAIDs could protect DA neurons from neurotoxic insults. NSAIDs can protect DA neurons against excitotoxicity (Casper et al. 2000), and against 6‐hydroxydopamine (6‐OHDA) toxicity (Carrasco et al. 2001). Here, we compared in primary mesencephalic/DA neuron cultures the effect of NSAIDs on the toxicity of 1‐methyl‐phenylpyridinium (MPP+) or 6‐OHDA. 6‐OHDA significantly (*p < 0.0001) increased PG production, whereas MPP+ did not (p < 0.05). We then compared the competitive/unspecific COX inhibitors ibuprofen and naproxen and the noncompetitive/unspecific inhibitor acetylsalicylic acid (ASA, aspirin) for their ability to protect DA neurons against either 6‐OHDA or MPP+ toxicity. Interestingly, all three nonselective COX inhibitors protected DA neurons in cultures against both 6‐OHDA and MPP+ (p < 0.05), despite the difference in PG induction by 6‐OHDA vs. MPP+. The selective COX‐2 inhibitor NS398 did protect DA neurons against 5 μm MPP+ (*p < 0.05), but failed to protect DA neurons against 5 μm 6‐OHDA (p < 0.05). Our results suggest that COX‐inhibitors may have neuroprotective benefits unrelated to inhibition of PG synthesis, and that 6‐OHDA and MPP+ have partially overlapping mechanisms of neurodegeneration possibly involving COX activity.Acknowledgement:  Supported, in part, by the International Federation for Parkinson's disease, NY, NY.
Poster Sessions BP01: Energy Metabolism. NMR investigation of metabolic alterations in the brain of thiamine‐deficient rats
Authors: Navarro D. , Zwingmann C. , Hazell A. S. , Leibfritz D. , Butterworth R. F. 
Published: July 2010

Thiamine deficiency (TD) results in region‐selective impairment of brain metabolism. Since thiamine is a cofactor for enzymes involved in glucose metabolism, 1H and 13C‐NMR was used to investigate metabolic fluxes through the major pathways of glucose metabolism in vulnerable (medial thalamus, MT; inferior colliculus, IC) and nonvulnerable brain structures of rats made thiamine deficient following treatment with the central thiamine antagonist pyrithiamine vs. pair‐fed controls. Symptomatic stages of TD resulted in decreased glutamate and GABA in MT an IC confirming previous biochemical studies. 13C‐isotopomer analysis revealed decreased de novo synthesis of [4–13C]glutamate (30%p < 0.02) and [2–13C]GABA	(60%p < 0.01) in MT and IC consistent with decreased activities of pyruvate‐ and α‐ketoglutarate dehydrogenases. These changes were accompanied by decreased consumption of glucose and increased synthesis of lactate from [1–13C]glucose confirming decreased mitochondrial metabolism. Accumulation of glyceraldehyde‐3‐phosphate suggested inhibition of glucose flux through the thiamine‐deficient enzyme transketolase. Onset of symptoms of TD and significant cell death was accompanied by decreased neuronal marker molecules NAA and NAAG in MT. Focal lactate accumulation resulting from decreased activities of mitochondrial thiamine‐dependent enzymes appears to play a key role in the pathogenesis of selective neuronal cell death in TD. [funded by CIHR Canada].
13C‐[2,4]‐b‐hydroxybutyrate metabolism in human brain
Authors: Pan J. W. , De Graaf R. A. , Rothman D. L. , Hetherington H. P. 
Published: July 2010

Although ketone metabolism is generally believed to be qualitatively similar to glucose consumption in the human brain, this has never been explicitly determined. We used 13C‐MR spectroscopy with infusions of	13C‐[2,4]‐b‐hydroxybutyrate (BHB, 200 mm, 100% enrichment) in overnight fasted adult subjects (n = 4) to examine the fate of this ketone. This was performed on a 2.1T Bruker spectrometer, volume size 6 × 4 × 6 cc3, previously determined to contain ∼ 56% gray, 39% white matter in normal adults. Results: The 2 h infusion increased plasma ketone levels from near negligible (baseline) to 2.25 ± 0.24 mm at steady state. Steady state 13C BHB levels were measured at 0.18 ± 0.04 mm. Similar to glucose, the 13C label appeared rapidly in the amino acid pools. The steady state fractional enrichment reached were: 13C‐4‐glutamate (4‐Glu), 6.78 ± 1.71%, 13C‐4‐glutamine (4‐Gln), 5.68 ± 1.84 and 13C‐3‐aspartate at 3.99 ± 0.57%. Discussion: The relatively low [BHB] of 0.18 ± 0.04 mm is an upper bound for tissue BHB, and is in agreement with the view that ketone consumption is largely regulated at the blood brain barrier in these nonfasted acutely hyperketonemic subjects. The general pattern of labeling of ketones is similar to that which has been previously seen with glucose. Steady state analysis of the ratio of 4‐Gln/4‐Glu suggests that ketones are predominantly used by neurons, and are consumed at a rate of 0.032 ± 0.009 mm/kg/min. This rate includes gray and white matter consumption. Dynamic modelling of the time courses of the brain 4‐Glu and 13C‐BHB, where gray matter ketone consumption is taken as three times greater than white matter (similar to that seen with glucose) gives an estimated upper bound for the flux of ketone oxidation in pure gray matter to be 0.041 ± 0.007 mm/kg/min.
Glutamatergic effects of dynorphin peptides on cultured oligodendrocytes
Authors: Knapp P. E. , Rizzo J. P. , Alimova Y. , Singh I. , Goody R. J. , Hauser K. F. 
Published: July 2010

Our previous work has shown that oligodendrocytes (OLs), in addition to neurons, can synthesize the endogenous opioid dynorphin A (dyn A). Opioid effects of dynorphin are preferentially mediated through kappa opioid receptors (KORs). Signalling through KORs appears to promote OL survival in culture since blockade of KORs with the specific antagonist nor‐binaltorphamine significantly reduces OL survival and exacerbates glutamate toxicity. Structure‐activity studies have shown that kappa ligand activity resides in the N‐terminus of dyn A derived‐peptides, while C‐terminal fragments exhibit glutamatergic effects on neurons through NMDA and/or AMPA/kainate receptors. The present study was undertaken to determine whether dynorphin peptides also have glutamatergic effects on OLs. Since OLs grown in vitro are thought to have an AMPA/kainate phenotype, OLs were treated with dyn A (1–17) or dyn A (2–17) in the presence or absence of CNQX. Survival of mature and immature OLs was assessed over 72 h using a sensitive repeated measures assay. Dyn A (1–17) had no effect on OL survival. Dyn A (2–17), a dyn A‐derived peptide with nominal opioid activity, significantly reduced the survival of both immature and mature OLs. The effect was completely reversible in mature OLs by addition of CNQX at 2 h prior to dyn A (2–17), but not by simultaneous addition of CNQX. Of great interest, CNQX was unable to reverse the toxicity of dyn A (2–17) on immature OLs, suggesting that dynorphin toxicity in this population is mediated via an alternate glutamate receptor type. CNQX alone had no effect on OL viability. Results suggest that elevated dynorphin levels in CNS disease and trauma may contribute to demyelinating pathologies.Acknowledgements: Supported by Natl. MS Soc. (PEK) & NIH DA 13559 (KFH).
Anti‐S‐nitrosocysteine antibodies in multiple sclerosis: emergence of a new marker of clinical activity
Authors: Boullerne A. I. , Schmidt S. , Brochet B. , Jensen M. A. , Petry K. G. , Arnason B. G. W. 
Published: July 2010

Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO‐related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S‐nitrosocysteine (SNO‐cysteine) and showed that anti‐SNO‐cysteine Abs of the IgM isotype are often present in the sera of MS patients (Boullerne et al. 1995, J. Neuroimmunol. 60, 117–124; Boullerne et al. 2002, J. Neurosci.22, 123–132). A seemingly identical Ab response directed against SNO‐cysteine in experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the MBP68‐84 peptide, peaked in serum one week before onset of clinical signs, suggesting a predictive role for clinical activity. In relapsing–remitting MS, we found elevated anti‐SNO‐cysteine Ab at times of relapse with normal values in most patients judged to be in remission or experiencing suspected but not definite attacks. The anti‐SNOcysteine Ab response returns to normal 2–3 months after a relapse. Anti‐SNO‐cysteine Ab levels are also elevated in progressive disease. Sixty per cent non treated secondary progressive MS (SPMS) were positive as were 50% of primary progressive MS. In treated SPMS patients anti‐SNOcysteine positivity was 45%. Anti‐SNOcysteine Ab levels correlated inversely with EDSS (Spearman coefficient r = −0.26, p = 0.01, n = 101), suggesting that the inflammatory component is reduced at high EDSS.Acknowledgements:  This work is supported by NMSS, Berlex and the Alan Friend Multiple Sclerosis Research Fund (B.G.W.A.).