Journal of Neurochemistry

Cover image for Vol. 133 Issue 5

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Jörg Schulz

Impact Factor: 4.244

ISI Journal Citation Reports © Ranking: 2013: 63/252 (Neurosciences); 74/291 (Biochemistry & Molecular Biology)

Online ISSN: 1471-4159

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  1. 1 - 50
  1. Original Articles

    1. p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing

      Rafael Andres Posada-Duque, Alejandro López-Tobón, Diego Piedrahita, Christian González-Billault and Gloria Patricia Cardona-Gomez

      Article first published online: 4 MAY 2015 | DOI: 10.1111/jnc.13127

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      CDK5 plays an important role in neurotransmission in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. Our findings suggest that p35/Rac1 signaling is critical in the CDK5 shRNAmiR-induced neuroprotection against glutamate neurotoxicity and is also correlated with the recovery of cognitive function in 3xTg-AD mice. CDK5 shRNAmiR blocks calpain activation, and the cleavage of p35 to p25 produced by glutamate, which generates neuroprotection in a p35 up-regulation dependent mode and its down-stream control of Rho GTPases, such as Rac1 and RhoA.

    2. Nidogen-1 is a common target of microRNAs MiR-192/215 in the pathogenesis of Hirschsprung's disease

      Dongmei Zhu, Hua Xie, Hongxing Li, Peng Cai, Hairong Zhu, Chao Xu, Pingfa Chen, Ankur Sharan, Yankai Xia and Weibing Tang

      Article first published online: 4 MAY 2015 | DOI: 10.1111/jnc.13118

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      We proposed the following cascade for the proposed mechanism of miR-192/215 in the pathogenesis of Hirschsprung disease (HSCR) by targeting Nidogen 1 (NID1). Aberrant expression of miR-192/215 inhibits cell migration and cell proliferation via NID1. We think the miR-192/miR-215/NID1 signaling pathway may play an important role in the pathogenesis of HSCR.

    3. Postnatal ethanol exposure alters levels of 2-arachidonylglycerol-metabolizing enzymes and pharmacological inhibition of monoacylglycerol lipase does not cause neurodegeneration in neonatal mice

      Shivakumar Subbanna, Delphine Psychoyos, Shan Xie and Balapal S. Basavarajappa

      Article first published online: 30 APR 2015 | DOI: 10.1111/jnc.13120

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      The consumption of ethanol by pregnant women may cause neurological abnormalities, affecting learning and memory processes in children, and are collectively described as fetal alcohol spectrum disorders (FASDs). In our study, ethanol treatment of postnatal day 7 (P7) mice significantly enhanced the levels of the developmentally relevant endocannabinoids anandamide (AEA) but not 2-arachidonylglycerol (2-AG), and induced widespread neurodegeneration, yet the reason for the lack of effects of ethanol on the 2-AG level is unknown. Here, the ethanol treatment of P7 mice causes the specific up-regulation of AEA-CB1R signaling over the 2-AG-CB1R pathway by the specific reorganization of the enzymes that synthesize (DAGL-α/β) and degrade (MAGL) 2-AG. This study demonstrates the neuro-regulatory role of 2-AG metabolizing enzymes in ethanol-induced neurodegeneration in neonatal mice.

    4. Methamphetamine acutely inhibits voltage-gated calcium channels but chronically up-regulates L-type channels

      Marilou A. Andres, Ian M. Cooke, Frederick P. Bellinger, Marla J. Berry, Maribel M. Zaporteza, Rachel H. Rueli, Stephanie M. Barayuga and Linda Chang

      Article first published online: 30 APR 2015 | DOI: 10.1111/jnc.13104

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      Methamphetamine (METH) exposure has both short- and long-term effects. Acutely, methamphetamine directly inhibits voltage-gated calcium channels. Chronically, neurons compensate by up-regulating the L-type Ca2+ channel gene, CACNA1C. This compensatory mechanism is mediated by transcription factors C-MYC and CREB, in which CREB is linked to the dopamine D1 receptor signaling pathway. These findings suggest Ca2+-mediated neurotoxicity owing to over-expression of calcium channels.

    5. Drebrin depletion alters neurotransmitter receptor levels in protein complexes, dendritic spine morphogenesis and memory-related synaptic plasticity in the mouse hippocampus

      Gangsoo Jung, Eun-Jung Kim, Ana Cicvaric, Sunetra Sase, Marion Gröger, Harald Höger, Fernando Jayson Sialana, Johannes Berger, Francisco J. Monje and Gert Lubec

      Article first published online: 29 APR 2015 | DOI: 10.1111/jnc.13119

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      We examined effect of genetic deletion of drebrin, which an actin-bundling key regulator of dendritic spine genesis and morphology, on dendritic spine density, maturity, level of complexes containing major brain receptors and also, in synaptic plasticity. These findings support for a role of drebrin in the regulation of memory-related synaptic plasticity and neurotransmitter receptors signaling in dendritic spines.

    6. Mice lacking glutamate carboxypeptidase II develop normally, but are less susceptible to traumatic brain injury

      Yang Gao, Siyi Xu, Zhenwen Cui, Mingkun Zhang, Yingying Lin, Lei Cai, Zhugang Wang, Xingguang Luo, Yan Zheng, Yong Wang, Qizhong Luo, Jiyao Jiang, Joseph H. Neale and Chunlong Zhong

      Article first published online: 28 APR 2015 | DOI: 10.1111/jnc.13123

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      The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) suppresses glutamate transmission through selective activation of pre-synaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3) after traumatic brain injury (TBI). However, synaptically released NAAG is hydrolyzed to form N-acetylaspartate and glutamate mainly by Glutamate carboxypeptidase II (GCPII), losing neuroprotective effect. In this study, we found that knock out of the GCPII gene is not embryonic lethal and affords histopathological protection with improved long-term behavioral outcomes after TBI.

    7. The regulation of p53 up-regulated modulator of apoptosis by JNK/c-Jun pathway in β-amyloid-induced neuron death

      Rumana Akhter, Priyankar Sanphui, Hrishita Das, Pampa Saha and Subhas Chandra Biswas

      Article first published online: 28 APR 2015 | DOI: 10.1111/jnc.13128

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      JNK/c-Jun pathway is shown to be activated in neurons of the Alzheimer's disease (AD) brain and plays a vital role in neuron death in AD models. However, downstream targets of c-Jun in this disease have not been thoroughly elucidated. Our study shows that two important pro-apoptotic proteins, Bim (Bcl-2 interacting mediator of cell death) and Puma (p53 up-regulated modulator of apoptosis) are targets of c-Jun in Aβ-treated neurons. We demonstrate that the JNK/c-jun pathway is activated, in cultures of cortical neurons following treatment with oligomeric Aβ and in AD transgenic mice, and that inhibition of this pathway by selective inhibitor blocks induction of Puma by Aβ. We have also observed functional co-operation of both JNK and p53 pathway in regulation of Puma under Aβ toxicity. Most importantly, we identified a novel AP1-binding site on rat puma gene which is necessary for direct binding of c-Jun with Puma promoter. Thus, our results suggest that both Bim and Puma are target of c-Jun and elucidate the intricate regulation of Puma expression by JNK/c-Jun and p53 pathways in neurons upon Aβ toxicity.

    8. Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat

      Nirmal Bhide, David Lindenbach, Christopher J. Barnum, Jessica A. George, Margaret A. Surrena and Christopher Bishop

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13125

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      We investigated the ability of the beta-adrenergic receptor (βAR) antagonist Propranolol to reduce drug-induced dyskinesia in hemi-parkinsonian rats. Dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA), but not D1 or D2 agonists was reduced by Propranolol. In vivo striatal microdialysis revealed that Propranolol's anti-dyskinetic effects were related to an attenuation of L-DOPA-induced dopamine (DA) efflux. These findings show that pre-synaptic βAR mediate L-DOPA-induced dyskinesia (LID) and highlight Propranolol's therapeutic potential.

    9. Efficient use of a translation start codon in BDNF exon I

      Indrek Koppel, Jürgen Tuvikene, Ingrid Lekk and Tõnis Timmusk

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13124

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      The brain-derived neurotrophic factor (BDNF) gene contains multiple untranslated 5′ exons alternatively spliced to one common protein-coding 3′ exon. However, exon I contains an in-frame ATG in a favorable translation context. Here, we show that use of this ATG is associated with more efficient protein synthesis than the commonly used ATG in exon IX.

    10. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors

      Siddhartha Dalvi, Hieu H. Nguyen, Ngoc On, Ryan W. Mitchell, Harold M. Aukema, Donald W. Miller and Grant M. Hatch

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13117

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      The blood–brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell® plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part, through increased prostaglandin E2 production from ARA which acted upon EP3 and EP4 receptors to increase HBMEC monolayer permeability.

    11. Neuroprotective effects of Argon are mediated via an ERK-1/2 dependent regulation of heme-oxygenase-1 in retinal ganglion cells

      Felix Ulbrich, Kai B. Kaufmann, Mark Coburn, Wolf Alexander Lagrèze, Martin Roesslein, Julia Biermann, Hartmut Buerkle, Torsten Loop and Ulrich Goebel

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13115

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      We proposed the following possible mechanism for Argon-mediated neuroprotection: Argon exerts its protective effects via an induction of an ERK with subsequent suppression of the heat shock response. In conclusion, ischemia and reperfusion injuries and subsequent neuronal apoptosis are attenuated. These novel findings may open up new opportunities for Argon as a therapeutic option, especially since Argon is not toxic.

    12. Endocytosis of GABAC receptors depends on subunit composition and is regulated by protein kinase C-ζ and protein phosphatase 1

      Lisa Linck, Jasmin Binder, Christian Haynl and Ralf Enz

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13126

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      Endocytosis of GABACR depends on subunit composition and is reciprocally regulated by protein kinase C-ζ and protein phosphatase 1 that are immobilized to intracellular receptor domains by scaffold proteins (ZIP3, PNUTS). Rho subunits of the pentameric GABACR (grey) offer intracellular phosphorylation sites (P). Our data propose a molecular mechanism that complements available electrophysiological data for GABACR turnover reported in the literature.

    13. Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders

      Jens O. Watzlawik, Robert J. Kahoud, Shermayne Ng, Meghan M. Painter, Louisa M. Papke, Laurie Zoecklein, Bharath Wootla, Arthur E. Warrington, William A. Carey and Moses Rodriguez

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13121

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      The human antibody HIgM12 stimulates neurite outgrowth in vitro and promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)-positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro-motor disorders including multiple sclerosis.

    14. Anatomical location of LPA1 activation and LPA phospholipid precursors in rodent and human brain

      Estibaliz González de San Román, Iván Manuel, María Teresa Giralt, Jerold Chun, Guillermo Estivill-Torrús, Fernando Rodríguez de Fonseca, Luis Javier Santín, Isidro Ferrer and Rafael Rodríguez-Puertas

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13112

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      Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein-coupled receptors (GPCR), LPA1 to LPA6. LPA evokes several responses in the central nervous system (CNS), including cortical development and folding, growth of the axonal cone and its retraction process. We used functional [35S]GTPγS autoradiography to verify the anatomical distribution of LPA1-binding sites in adult rodent and human brain. The distribution of LPA1 receptors in rat, mouse and human brains show the highest activity in white matter myelinated areas. The basal and LPA-evoked activities are abolished in MaLPA1-null mice. The phospholipid precursors of LPA are localized by MALDI-IMS. The anatomical distribution of LPA precursors in rodent and human brain suggests a relationship with functional LPA1 receptors.

    15. Neuronally produced versican V2 renders C-fiber nociceptors IB4-positive

      Oliver Bogen, Olaf Bender, Jana Löwe, Wolfgang Blenau, Beatrice Thevis, Wolfgang Schröder, Richard U. Margolis, Jon D. Levine and Ferdinand Hucho

      Article first published online: 27 APR 2015 | DOI: 10.1111/jnc.13113

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      A subset of nociceptors, the GDNF-dependent non-peptidergic C-fibers can be characterized by its reactivity for isolectin B4 (IB4), a plant lectin from Griffonia simplicifolia. We have previously demonstrated that versican V2 binds IB4 in a Ca2 + -dependent manner. However, given that versican is thought to be the product of glial cells, it was questionable whether versican V2 can be accountable for the IB4-reactivity of this subset of nociceptors. The results presented here prove – for the first time – a neuronal origin of versican and suggest that versican V2 is the molecule that renders GDNF-dependent non-peptidergic C-fibers IB4-positive.

    16. 1–42 oligomer-induced leakage in an in vitro blood–brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins

      Wenbin Wan, Lan Cao, Lumei Liu, Chunyan Zhang, Bill Kalionis, Xiantao Tai, Yaming Li and Shijin Xia

      Article first published online: 24 APR 2015 | DOI: 10.1111/jnc.13122

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      To reveal the role of RAGE in blood–brain barrier (BBB) disruption in Alzheimer's disease (AD), we employed an monolayer BBB model comprising bEnd.3 cell and found that BBB leakage was induced by treatment with amyloid-β (Aβ), and the levels of tight junction (TJ) scaffold proteins including ZO-1, Claudin-5, and Occludin were decreased. Using receptor for advanced glycation end-products (RAGE) neutralizing polyclonal antibody and siRNA, we confirmed that RAGE played an important role in Aβ-induced BBB leakage and alterations of TJ scaffold proteins and in the up-regulation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

    17. TGFβ1 inhibits IFNγ-mediated microglia activation and protects mDA neurons from IFNγ-driven neurotoxicity

      Xiaolai Zhou, Tanja Zöller, Kerstin Krieglstein and Björn Spittau

      Article first published online: 23 APR 2015 | DOI: 10.1111/jnc.13111

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      Interferon γ (IFNγ) is a potent pro-inflammatory factor that triggers the activation of microglia and the subsequent release of neurotoxic factors. Transforming growth factor β1 (TGFβ1) is able to inhibit the IFNγ-mediated activation of microglia, which is characterized by the release of nitric oxide (NO) and tumor necrosis factor α (TNFα). By decreasing the expression of IFNγ-induced genes as well as the signaling receptor IFNγR1, TGFβ1 reduces the responsiveness of microglia towards IFNγ. In mixed neuron-glia cultures, TGFβ1 protects midbrain dopaminergic (mDA) neurons from IFNγ-induced neurotoxicity.

  2. Reviews

    1. You have free access to this content
      Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function

      Leif Hertz, Ye Chen and Helle S. Waagepetersen

      Article first published online: 23 APR 2015 | DOI: 10.1111/jnc.13107

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      Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aβ-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic β-hydroxybutyrate doses are too low to reduce neuronally released glutamate.

  3. Original Articles

    1. Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel

      Ruchi Yadav, Xisheng Yan, Dylan W. Maixner, Mei Gao and Han-Rong Weng

      Article first published online: 23 APR 2015 | DOI: 10.1111/jnc.13103

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      Patients receiving paclitaxel for cancer therapy often develop neuropathic pain and have a reduced quality of life. In this study, we demonstrated that animals treated with paclitaxel develop neuropathic pain, have enhancements of GABA transporter-1 protein expression and global GABA uptake, as well as suppression of GABAergic tonic inhibition in the spinal dorsal horn. Pharmacological inhibition of GABA transporter-1 ameliorates the paclitaxel-induced suppression of GABAergic tonic inhibition and neuropathic pain. Thus, targeting GAT-1 transporters for reversing GABAergic disinhibition in the spinal dorsal horn could be a useful approach for treating paclitaxel-induced neuropathic pain.

    2. Lanthionine ketimine ester provides benefit in a mouse model of multiple sclerosis

      Jeffrey L. Dupree, Paul E. Polak, Kenneth Hensley, Dale Pelligrino and Douglas L. Feinstein

      Article first published online: 22 APR 2015 | DOI: 10.1111/jnc.13114

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      Only few drugs have been shown to reduce neurodegeneration in multiple sclerosis (MS). We report that LKE (lanthionine ketimine ethyl-ester, a derivative of the amino acid lanthionine) reduced clinical signs in a mouse model of chronic MS, and also reduced neurodegeneration and axonal damage in the spinal cord and optic nerve (shown in the graphic). These effects were associated with changes in levels and phosphorylation state of CRMP2 (collapsin response mediator protein 2), which has known actions on axon growth. These findings suggest that LKE may be a candidate for testing in progressive forms of MS.

  4. Reviews

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      Modulation of actin dynamics by Rac1 to target cognitive function

      Maria V. Tejada-Simon

      Article first published online: 22 APR 2015 | DOI: 10.1111/jnc.13100

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      While the small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in different type of cells, it appears to be also required for learning and the formation of memories in the brain. Abnormal regulation of this protein has been associated with cognitive disabilities, atypical synaptic plasticity and abnormal morphology of dendritic spines in certain neurodevelopmental disorders. Thus, modulation of Rac1 activity using novel inhibitors might be a strategy to reestablish cognitive function.

  5. Original Articles

    1. The role of parkinson's disease-associated receptor GPR37 in the hippocampus: functional interplay with the adenosinergic system

      João P. Lopes, Xavier Morató, Carolina Souza, Cindy Pinhal, Nuno J. Machado, Paula M. Canas, Henrique B. Silva, Igor Stagljar, Jorge Gandía, Víctor Fernández-Dueñas, Rafael Luján, Rodrigo A. Cunha and Francisco Ciruela

      Article first published online: 21 APR 2015 | DOI: 10.1111/jnc.13109

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      GPR37 is an orphan G protein-coupled receptor widely expressed in the hippocampus and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals. This orphan receptor per se does not appear to directly control the learning and memory processes; however knocking-out GPR37 triggers anxiolytic-like effects and sensitizes mice to hippocampal A2AR-mediated signalling.

    2. Development of mature BDNF-specific sandwich ELISA

      Yoon Lim, Jin-Hua Zhong and Xin-Fu Zhou

      Article first published online: 21 APR 2015 | DOI: 10.1111/jnc.13108

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      As the function of proBDNF differs from mBDNF (mature BDNF), it is necessary to establish an ELISA specific for the detection of mBDNF. Here, we present a novel sandwich ELISA which detects mBDNF with high specificity. This new ELISA will be useful for the measurement of mBDNF levels with high specificity in various human and animal tissues. proBDNF, precursor of BDNF; BDNF, brain-derived neurotrophic factor; NT-3, neurotrophin-3; NT-4, neurotrophin-4; NGF, nerve growth factor.

    3. Identification of P-glycoprotein co-fractionating proteins and specific binding partners in rat brain microvessels

      Margaret E. Tome, Charles P. Schaefer, Leigh M. Jacobs, Yifeng Zhang, Joseph M. Herndon, Fabian O. Matty and Thomas P. Davis

      Article first published online: 21 APR 2015 | DOI: 10.1111/jnc.13106

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      This model depicts two types of P-glycoprotein (PgP)-containing caveolae. Rat brain microvessels contain two unique pools of PgP that are of different densities. Each pool co-fractionates with three caveolar proteins suggesting there are two populations of caveolae that contain PgP. The two caveolar populations differ in density indicating they have a different structure, lipoprotein content or intracellular location. Our model includes two newly identified PgP-binding partners, Hsc71 and protein disulfide isomerase, in rat brain microvessels.

    4. Vinexin-β deficiency protects against cerebral ischaemia/reperfusion injury by inhibiting neuronal apoptosis

      Mingchang Li, Sen Guo, Peng Zhang, Jun Gong, Ankang Zheng, Yan Zhang and Hongliang Li

      Article first published online: 19 APR 2015 | DOI: 10.1111/jnc.13110

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      Vinexin-β is an adaptor protein that regulates cell adhesion and cytoskeletal organization. We revealed that Vinexin-β-deficient mice are potently protected against ischaemia/reperfusion (I/R) injury. The protective effect is mediated through inhibiting neuronal apoptosis, which may occur via the up-regulation of Akt signalling. These findings suggest Vinexin-β as a novel regulator of I/R injury and attractive therapeutic target for the prevention of stroke.

    5. Kisspeptin1 modulates odorant-evoked fear response via two serotonin receptor subtypes (5-HT1A and 5-HT2) in zebrafish

      Fatima M. Nathan, Satoshi Ogawa and Ishwar S. Parhar

      Article first published online: 17 APR 2015 | DOI: 10.1111/jnc.13105

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      Kiss1 peptide intracranially (IC) administrated has been shown to decrease olfactory, alarm substance (AS)-evoked fear response. Blockade of the 5-HT1A receptor utilizing WAY 100635 (0.28 mg/kg) and the 5-HT1 and 5-HT2 receptor utilizing methysergide (92.79 mg/kg) produced increased AS-evoked fear responses that were unable to be overcome even during the recovery period. Blockade of this 5-HT system followed by Kiss1 administration showed that the peptide was unable to recover the anxiolytic effects upon 5-HT1A blocking using WAY 100635 with the exception of freezing behaviour while methysergide significantly blocked all the anxiolytic effects of Kiss1. These findings implicate that Kiss1 could modulate AS-evoked fear responses mediated by 5-HT1A and 5-HT2 receptors.

    6. Regulation of peroxisome proliferator-activated receptors (PPAR) α and -γ of rat brain astrocytes in the course of activation by toll-like receptor agonists

      Dmitry V. Chistyakov, Stepan E. Aleshin, Alina A. Astakhova, Marina G. Sergeeva and Georg Reiser

      Article first published online: 16 APR 2015 | DOI: 10.1111/jnc.13101

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      Astrocytes have the triad of PPARα, PPARβ/δ, and PPARγ in regulation of proinflammatory responses. Activation of Toll-like receptors (TLR) leads to PPARβ/δ overexpression, PPARα and PPARγ suppression via TLR/NF-κB pathway on mRNA, protein and activity levels. Mitogen-activated protein kinases (MAPK) p38 and JNK are involved in regulation of PPAR expression. p38 MAPK plays a special role in stabilization of PPAR mRNA.

    7. Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia-like conditions: key roles of the transcription factors GATA2, Sp1 and TBP

      Vinayak Gupta, Abrar A. Khan, Binu K. Sasi and Nitish R. Mahapatra

      Article first published online: 16 APR 2015 | DOI: 10.1111/jnc.13099

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      Dysregulation of monoamine oxidase A (MAOA) have been implicated in several behavioral and neuronal disease states. Here, we identified three crucial transcription factors (GATA2, Sp1 and TBP) that regulate MAOA gene expression in a coordinated manner. Aberrant MAOA expression under pathophysiological conditions including inflammation and ischemia is mediated by altered binding of GATA2/Sp1/TBP with MAOA proximal promoter. Thus, these findings provide new insights into pathogenesis of several common diseases. GATA2, GATA-binding protein 2; Sp1, specificity protein 1; TBP, TATA-binding protein.

    8. AAV-mediated expression of BAG1 and ROCK2-shRNA promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury

      Malleswari Challagundla, Jan Christoph Koch, Vinicius Toledo Ribas, Uwe Michel, Sebastian Kügler, Thomas Ostendorf, Frank Bradke, Hans Werner Müller, Mathias Bähr and Paul Lingor

      Article first published online: 13 APR 2015 | DOI: 10.1111/jnc.13102

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      Understanding the mechanisms involved in neuronal survival and axonal regeneration after spinal cord injury (SCI) is pivotal for the development of new therapies. We showed that over-expression of BAG1 (Bcl-2-associated athanogene-1) and down-regulation of ROCK2 (Rho-associated protein kinase) improve neuronal survival and axonal sprouting after SCI. Our results imply that BAG1 and ROCK2 represent interesting molecular targets that can be used in future therapeutic strategies for the treatment of SCI. AAV = adeno-associated virus.

    9. Fastigial nucleus stimulation regulates neuroprotection via induction of a novel microRNA, rno-miR-676-1, in middle cerebral artery occlusion rats

      Xiao-Min Pang, Jing-Li Liu, Jin-Pin Li, Li-Gang Huang, Lei Zhang, Hui-Yao Xiang, Ling-Bo Feng, Chun-Yong Chen, Sheng-Hua Li and Sheng-You Su

      Article first published online: 10 APR 2015 | DOI: 10.1111/jnc.13094

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      MicroRNA (miRNA) is defined as a small non-coding RNA that fulfills both the expression and biogenesis criteria. Here, we describe a novel miRNA in the rat ischemic cortex expressed after 1 h of fastigial nucleus stimulation (FNS). The miRNA was functionally characterized by secondary structure, quantitative expression, the conservation analysis, target gene analysis, and biological functions. We consider rno-miR-676-1 to be a true microRNA and present evidence for its neuroprotective effects exerted after induction by FNS.

    10. miR-210 mediates vagus nerve stimulation-induced antioxidant stress and anti-apoptosis reactions following cerebral ischemia/reperfusion injury in rats

      Ying Jiang, Longling Li, Xiaodan Tan, Bin Liu, Yanhong Zhang and Changqing Li

      Article first published online: 8 APR 2015 | DOI: 10.1111/jnc.13097

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      Since approved by the FDA in 1997, vagus nerve stimulation (VNS) has proven to be a safe and effective treatment for refractory epilepsy and resistant depression. Recent studies have found that VNS also provided neuroprotective effects against ischemic injury in a rat stroke model. We showed that miR-210 played an important role in the antioxidant stress and anti-apoptosis responses induced by VNS. This is the first report showing the effects of VNS at the mRNA level. Therefore, VNS represents a promising candidate treatment for ischemic stroke patients. Schematic view of the role of miR210 mediated in the protective effects of the VNS on the acute cerebral ischemia. VNS acts to activate neuronal and astrocytes a7nAchR , inhibits the apoptosis and oxidant stress responses possibly associated with increased Akt phosphorylation and miR210 expression.

    11. Major involvement of Na+-dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells

      Yasuo Uchida, Katsuaki Ito, Sumio Ohtsuki, Yoshiyuki Kubo, Takashi Suzuki and Tetsuya Terasaki

      Article first published online: 8 APR 2015 | DOI: 10.1111/jnc.13092

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      In humans, it was unclear (not concluded) about what transport system at the blood–brain barrier (BBB) is responsible for the brain uptakes of two vitamins, biotin and pantothenic acid, which are necessary for brain proper function. This study clarified for the first time that the solute carrier 5A6/Na+-dependent multivitamin transporter SLC5A6/SMVT is responsible for the supplies of biotin and pantothenic acid into brain across the BBB in humans. DHA, docosahexaenoic acid; NSAID, non-steroidal anti-inflammatory drug; PGE2, prostaglandin E2.

    12. Alpha-ketoglutarate dehydrogenase complex-dependent succinylation of proteins in neurons and neuronal cell lines

      Gary E. Gibson, Hui Xu, Huan-Lian Chen, Wei Chen, Travis T. Denton and Sheng Zhang

      Article first published online: 8 APR 2015 | DOI: 10.1111/jnc.13096

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      Reversible post-translation modifications of proteins are common and may regulate many processes. Succinylation of proteins occurs and causes large changes in the structure of proteins. However, the source of the succinyl groups, the targets, and the consequences of these modifications on other proteins remains unknown. The results demonstrate that the mitochondrial α-ketoglutarate dehydrogenase complex (KGDHC) can succinylate multiple mitochondrial proteins and alter their function. Succinylation appears to be a major signaling system and it can be mediated by KGDHC.

    13. The intracellular domain of L1CAM binds to casein kinase 2α and is neuroprotective via inhibition of the tumor suppressors PTEN and p53

      Yan Wang and Melitta Schachner

      Article first published online: 25 MAR 2015 | DOI: 10.1111/jnc.13083

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      L1CAM (L1 cell adhesion molecule) is implicated in neural functions through the cognate src/MAP kinase signaling pathway. We now describe a novel signaling platform operating via the alpha subunit of casein kinase 2 which binds to the intracellular domain of L1. Knockdown of L1CAM leads to increased levels of tumor suppressor PTEN (phosphatase and tensin homolog) and p53, known to inhibit neuritogenesis in vitro and recovery from trauma in vivo. By activating this enzyme, L1CAM adds to its beneficial functions by decreasing the levels of PTEN and p53.

    14. Receptive range analysis of a mouse odorant receptor subfamily

      Jingyi Li, Rafi Haddad, Vanessa Santos, Selvan Bavan and Charles W. Luetje

      Article first published online: 25 MAR 2015 | DOI: 10.1111/jnc.13095

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      We screened a small group of mouse odorant receptors (MORs) with a diverse odorant panel to identify a new odorant-OR pairing (unsaturated aldehydes and MOR263-3), then extensively screened a series of additional MORs related to MOR263-3 in various ways. MORs related by phylogenetic analysis had odorant specificities that overlapped with that of MOR263-3, but MOR171-17, predicted to be functionally related to MOR263-3 by an alternative bioinformatic analysis, had a distinct odorant specificity.

    15. You have full text access to this OnlineOpen article
      Expression of the synaptic exocytosis-regulating molecule complexin 2 in taste buds and its participation in peripheral taste transduction

      Azusa Kurokawa, Masataka Narukawa, Makoto Ohmoto, Joto Yoshimoto, Keiko Abe and Takumi Misaka

      Article first published online: 23 MAR 2015 | DOI: 10.1111/jnc.13073

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      A part of taste information is thought to be transmitted via synapses. However, the molecular mechanisms have not been fully elucidated. To identify molecules that participate in synaptic taste transduction, we investigated complexins (Cplxs) expression in taste bud cells. Strong expression of Cplx2 mRNA was detected in taste bud cells. Furthermore, taste responses to some sour stimuli in CPLX2- knockout mice were significantly lower than those in wild-type mice. These suggested that CPLX2 participated in synaptic taste transduction.

    16. Characterization of traumatic brain injury in human brains reveals distinct cellular and molecular changes in contusion and pericontusion

      Gangadharappa Harish, Anita Mahadevan, Nupur Pruthi, Sreelakshmi K. Sreenivasamurthy, Vinuth N. Puttamallesh, Thottethodi Subrahmanya Keshava Prasad, Susarla Krishna Shankar and Muchukunte Mukunda Srinivas Bharath

      Article first published online: 20 MAR 2015 | DOI: 10.1111/jnc.13082

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      We have characterized the primary injury in human traumatic brain injury (TBI). Contusions (Ct) – the injury core displayed hemorrhages, inflammation, and astrogliosis, while the surrounding pericontusion (PC) revealed edema, vacuolation, microglial activation, axonal loss, and dystrophy. Proteomic analysis demonstrated altered immune response, synaptic and mitochondrial dysfunction in Ct, and altered regulation of neurogenesis and cytoskeletal architecture in PC. Ct displayed more oxidative damage, mitochondrial, and synaptic dysfunction compared to PC.

    17. Recombinant adeno-associated viral (rAAV) vectors mediate efficient gene transduction in cultured neonatal and adult microglia

      Wei Su, John Kang, Bryce Sopher, James Gillespie, Macarena S. Aloi, Guy L. Odom, Stephanie Hopkins, Amanda Case, David B. Wang, Jeffrey S. Chamberlain and Gwenn A. Garden

      Article first published online: 20 MAR 2015 | DOI: 10.1111/jnc.13081

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      Neonatal microglia are functionally distinct from adult microglia, although the majority of in vitro studies utilize rodent neonatal microglia cultures because of difficulties of culturing adult cells. In addition, cultured microglia are refractory to most methods for modifying gene expression. Here, we developed a novel protocol for culturing adult microglia and evaluated the feasibility and efficiency of utilizing Recombinant Adeno-Associated Virus (rAAV) to modulate gene expression in cultured microglia.

    18. Amyloid β-abrogated TrkA ubiquitination in PC12 cells analogous to Alzheimer's disease

      Chen Zheng, Thangiah Geetha, Marla Gearing and Jeganathan Ramesh Babu

      Article first published online: 19 MAR 2015 | DOI: 10.1111/jnc.13076

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      Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75NTR, p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin.

    19. Functional characterization of mutants in the transmembrane domains of the rat P2X7 receptor that regulate pore conductivity and agonist sensitivity

      Marie Jindrichova, Anirban Bhattacharya, Marian Rupert, Petr Skopek, Tomas Obsil and Hana Zemkova

      Article first published online: 18 MAR 2015 | DOI: 10.1111/jnc.13078

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      We investigated the mechanism of the proapoptotic receptor P2X7R's large pore opening and its sensitization. We found that aromatic residues in the upper part of the first transmembrane domain (TM1) are critical for both the P2X7R channel pore opening and receptor sensitization, and residues located at or below the intersection of the second transmembrane domains (TM2) control the rate of pore opening. These findings identify new residues involved in pore formation of P2X7R.

    20. Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced Müller cell disruption

      Ling Zhu, Weiyong Shen, Brian Lyons, Ying Wang, Fanfan Zhou and Mark C. Gillies

      Article first published online: 15 MAR 2015 | DOI: 10.1111/jnc.13075

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      This study reports down-regulation of inter-photoreceptor retinoid-binding protein (IRBP) in photoreceptors and retinoid cycle derangement after Müller cell disruption in a transgenic mouse model. The findings indicate that Müller cells communicate with photoreceptors in response to stress by secreting soluble protein factor(s). We propose that down-regulation of IRBP may represent an early and novel pathogenic mechanism in degenerative retinal diseases.

    21. Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease

      Carolina Alquézar, Estíbaliz Barrio, Noemí Esteras, Ana de la Encarnación, Fernando Bartolomé, José A. Molina and Ángeles Martín-Requero

      Article first published online: 15 MAR 2015 | DOI: 10.1111/jnc.13070

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      We report here that peripheral cells from Parkinson's disease (PD) patients show an enhanced proliferative activity due to the activation of cyclin D3/CDK6-mediated phosphorylation of retinoblastoma protein (pRb). Treatment of PD lymphoblasts with inhibitors of histone deacetylases like suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), or with rapamycin, inhibitor of mechanistic target of rapamycin (mTOR) normalized the proliferation of PD lymphoblasts by preventing the over-activation of the cyclin D3/CDK6/pRb cascade. These drugs were shown to have neuroprotective effects in both human neuroblastoma SH-SY5Y cells and primary rat mid-brain dopaminergic neuronal cultures toxicity induced by 6-hidroxydopamine. Considering that these drugs are already used in clinic for treatment of other diseases with good tolerance, it seems reasonable to believe that the repositioning of these drugs toward PD holds promise as a novel therapeutic strategy.

    22. Ghrelin regulates phasic dopamine and nucleus accumbens signaling evoked by food-predictive stimuli

      Jackson J. Cone, Jamie D. Roitman and Mitchell F. Roitman

      Article first published online: 13 MAR 2015 | DOI: 10.1111/jnc.13080

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      Cues that predict food availability powerfully regulate food-seeking behavior. Here we show that cue-evoked changes in both nucleus accumbens (NAc) dopamine (DA) and NAc cell activity are modulated by intra-cranial infusions of the stomach hormone ghrelin - a hormone known to act centrally to promote food intake. These data demonstrate that hormones associated with physiological state (i.e., hunger) can affect encoding of food-predictive cues in brain regions that drive food-motivated behavior.

    23. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid

      Dongxian Zhang, Brian Lee, Anthony Nutter, Paul Song, Nima Dolatabadi, James Parker, Sara Sanz-Blasco, Traci Newmeyer, Rajesh Ambasudhan, Scott R. McKercher, Eliezer Masliah and Stuart A. Lipton

      Article first published online: 11 MAR 2015 | DOI: 10.1111/jnc.13074

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      Cyanide, a potential bioterrorist agent, can produce a chronic delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Here, cyanide poisoning treated with the proelectrophillic compound carnosic acid, results in reduced neuronal cell death in both in vitro and in vivo models through activation of the Nrf2/ARE transcriptional pathway. Carnosic acid is therefore a potential treatment for the toxic central nervous system (CNS) effects of cyanide poisoning. ARE, antioxidant responsive element; Nrf2 (NFE2L2, Nuclear factor (erythroid-derived 2)-like 2).

  6. Reviews

    1. You have free access to this content
      Microglia and neuroprotection

      Zhihong Chen and Bruce D. Trapp

      Article first published online: 10 MAR 2015 | DOI: 10.1111/jnc.13062

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      Microglia are the resident innate immune cells of the CNS. Despite the traditional view of microglia as being destructive in neurological diseases, recent studies have shown that they maintain tissue homeostasis and protect the CNS under various pathological conditions. They achieve so by clearing debris, promoting neurogenesis, suppressing inflammation and stripping inhibitory synapses. This review summarizes recent advances of our understanding on the multi-dimensional neuroprotective roles of microglia.

  7. Original Articles

    1. APLP1 and APLP2, members of the APP family of proteins, behave similarly to APP in that they associate with NMDA receptors and enhance NMDA receptor surface expression

      Sarah L. Cousins, Wei Dai and F. Anne Stephenson

      Article first published online: 8 MAR 2015 | DOI: 10.1111/jnc.13063

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      Amyloid precursor protein (APP) has been shown to associate with N-methyl-d-aspartate (NMDA) receptors and to enhance their cell surface expression. Here, we show that the other members of the APP family, APLP1 and APLP2, behave similarly to APP in that they both associate with assembled NMDA receptors in the endoplasmic reticulum via their interaction with the NMDA receptor subunit, GluN1 and, they enhance receptor cell surface expression. Alternative scenarios are depicted since it is to be determined if respective associations are direct.

    2. Heat shock protein responses to aging and proteotoxicity in the olfactory bulb

      Tyler S. Crum, Amanda M. Gleixner, Jessica M. Posimo, Daniel M. Mason, Matthew T. Broeren, Scott D. Heinemann, Peter Wipf, Jeffrey L. Brodsky and Rehana K. Leak

      Article first published online: 5 MAR 2015 | DOI: 10.1111/jnc.13041

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      The olfactory bulb is affected in the early phases of many age-related neurodegenerative disorders. Here, we described the impact of aging on multiple heat shock proteins (Hsps), such as Hsp70, in the female rat olfactory bulb in vivo. Using multiple proteasome and Hsp70 inhibitors (see schematic), we found that proteotoxicity elicited a compensatory increase in Hsp70 in primary olfactory bulb cells in vitro. Hsp70 then reduced the proteotoxic buildup of ubiquitinated proteins and robustly protected against cell death according to three independent viability assays. Thus, olfactory bulb neurons can mount impressive natural adaptations to proteotoxic injury, perhaps explaining why neurodegenerative disorders are so delayed in onset and so slow to progress.

    3. Schwann cells contribute to neurodegeneration in transthyretin amyloidosis

      Tatsufumi Murakami, Kazunori Sango, Kazuhiko Watabe, Naoko Niimi, Shizuka Takaku, Zhenghua Li, Ken-ichi Yamamura and Yoshihide Sunada

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13068

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      We established a spontaneously immortalized Schwann cell line derived from familial amyloidotic polyneuropathy transgenic mice. Conditioned medium from the cells contained variant transthyretin (TTR), and inhibited neurite outgrowth of neurons. TTR aggregates were observed in the Schwann cells and satellite cells of aged mice. Proteasome inhibition induced TTR aggregates as aggresomes in the cultured cells. These results support the hypothesis that Schwann cells contribute to neurodegeneration in familial amyloidotic polyneuropathy (FAP).

    4. Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine

      Li-Min Mao, Bing Xue, Dao-Zhong Jin and John Q. Wang

      Article first published online: 2 MAR 2015 | DOI: 10.1111/jnc.13067

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      Acute injection of amphetamine increased phosphorylation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunits at a protein kinase A (PKA)-sensitive site (S845) in the rat hippocampus. This increase was dose- and time-dependent and correlated with an increase in surface GluA1 expression. Thus, amphetamine can upregulate GluA1 phosphorylation and surface trafficking of GluA1 in hippocampal neurons in vivo.

    5. Exosome-mediated inflammasome signaling after central nervous system injury

      Juan Pablo de Rivero Vaccari, Frank Brand III, Stephanie Adamczak, Stephanie W. Lee, Jon Perez-Barcena, Michael Y. Wang, M. Ross Bullock, W. Dalton Dietrich and Robert W. Keane

      Article first published online: 1 MAR 2015 | DOI: 10.1111/jnc.13036

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      We propose the following signaling cascade for inflammasome activation in peripheral tissues after CNS injury: CNS trauma induces inflammasome activation in the nervous system and secretion of exosomes containing inflammasome protein cargo into cerebral spinal fluid. The inflammasome containing exosomes then fuse with target cells to activate the innate immune response in peripheral tissues. We suggest that these findings may be used to develop new therapeutics to treat the devastating inflammation and cell destruction evoked by CNS injuries. IL-1β and IL-18 = pro-inflammatory cytokines.

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