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Journal of Neurochemistry

Cover image for Vol. 125 Issue 1

April 2013

Volume 125, Issue 1

Pages 1–171

  1. EDITORIAL HIGHLIGHTS

    1. Top of page
    2. EDITORIAL HIGHLIGHTS
    3. ORIGINAL ARTICLES
    1. You have free access to this content
      Dissecting γ-secretase function (pages 1–3)

      Lucía Chávez-Gutiérrez

      Article first published online: 21 MAR 2013 | DOI: 10.1111/jnc.12077

      Read the full article ‘Important functional role of residue x of the presenilin GxGD protease active site motif for APP substrate cleavage specificity and substrate selectivity of γ-secretase’ on doi: 10.1111/jnc.12124.

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      The anti-AD cookbook: a new recipe (pages 4–6)

      Natalia V. Gulyaeva and Mikhail Y. Stepanichev

      Article first published online: 21 MAR 2013 | DOI: 10.1111/jnc.12138

      Read the full article ‘Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease’ on doi: 10.1111/jnc.12127.

  2. ORIGINAL ARTICLES

    1. Top of page
    2. EDITORIAL HIGHLIGHTS
    3. ORIGINAL ARTICLES
    1. Signal Transduction & Synaptic Transmission

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      Subunit-dependent inhibition and potentiation of 5-HT3 receptor by the anticancer drug, topotecan (pages 7–15)

      Yukiko Nakamura, Yusuke Ishida, Takahiro Yamada, Makoto Kondo and Shoichi Shimada

      Article first published online: 31 JAN 2013 | DOI: 10.1111/jnc.12146

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      We have shown that an established anti-cancer drug, topotecan, has a previously unknown pharmacological feature: the ability to act as an inhibitor of 5-HT3A receptors but as an enhancer of the 5-HT3AB receptors. The potentiating effect was reduced in the receptors containing Y129S polymorphic variant of 5-HT3B subunit. These finding could explain individual differences in sensitivity to topotecan-induced nausea and vomiting.

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      Stress-induced changes in adrenal neuropeptide Y expression are regulated by a negative feedback loop (pages 16–25)

      Qian Wang and Matthew D. Whim

      Article first published online: 17 FEB 2013 | DOI: 10.1111/jnc.12150

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      Acute stress alters adrenal neuropeptide Y expression via a negative feedback loop

      Stress increases the expression of the neuromodulator NPY in the adrenal medulla but the pathways mediating this effect are not clear. We find that under basal (stress-free) conditions, a negative feedback loop involving NPY release and the activation of Y2 receptors tonically inhibits adrenal NPY expression. Because stress overrides this inhibitory effect it may provide an efficient way to ensure the adrenal levels of NPY do not decline after intense sympathetic activity.

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      5-Hydroxytryptamine type 7 receptor neuroprotection against NMDA-induced excitotoxicity is PDGFβ receptor dependent (pages 26–36)

      Maryam S. Vasefi, Jeff S. Kruk, John J. Heikkila and Michael A. Beazely

      Article first published online: 13 FEB 2013 | DOI: 10.1111/jnc.12157

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      Growth factor receptors in the CNS are protective against several neuronal insults. However, it is difficult to introduce growth factors into the brain because of their large size. We identify a pathway whereby serotonin (5-HT) 7 receptor agonists (small organic molecules) increase the expression of the platelet-derived growth factor (PDGF) receptor to protect neurons against toxicity.

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      A comparison of the signalling properties of two tyramine receptors from Drosophila (pages 37–48)

      Asha Bayliss, Giuliana Roselli and Peter D. Evans

      Article first published online: 14 FEB 2013 | DOI: 10.1111/jnc.12158

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      In invertebrates, the phenolamines, tyramine and octopamine, mediate roles usually associated with the vertebrate catecholamines, noradrenaline and adrenaline. Drosophila melanogaster expresses two closely structurally related putative tyramine-activated GPCRs (CG7431, CG16766). We show that the two receptors have different pharmacological signalling and internalization properties. CG16766 orthologues only occur in Drosophila species, whereas CG7431 orthologues also occur in other insect species.

    5. Brain Development & Cell Differentiation

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      Neuronal Galectin-4 is required for axon growth and for the organization of axonal membrane L1 delivery and clustering (pages 49–62)

      Silvia Velasco, Natalia Díez-Revuelta, Teresa Hernández-Iglesias, Herbert Kaltner, Sabine André, Hans-Joachim Gabius and José Abad-Rodríguez

      Article first published online: 3 FEB 2013 | DOI: 10.1111/jnc.12148

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      Galectin-4 sorts to axon plasma membrane segments by binding to sulfatide-containing axonal carriers and, being bivalent, it organizes the transport of L1, and likely other glycoproteins, by attaching them to the same carriers specifically through their LacNAc termini. We propose that this mechanism would underlie L1 functional clustered organization on the axon membrane, required for proper axon growth.

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      Aging is associated with altered inflammatory, arachidonic acid cascade, and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex (pages 63–73)

      Vasken L. Keleshian, Hiren R. Modi, Stanley I. Rapoport and Jagadeesh S. Rao

      Article first published online: 17 FEB 2013 | DOI: 10.1111/jnc.12153

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      Brain aging involves balance between protective and progressive factors. Increased expression of iPLA2 and cytochrome p450 epoxygenase and their products are neuroprotective. At the same time, increased neuroinflammatory markers and altered pro and anti-apoptotic factors could contribute to loss of synaptic proteins. This may lead to altered synaptic plasticity. These molecular alterations are influenced by gene specific epigenetic modifications.

    7. Neuroinflammation & Neuroimmunology

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      Ly6C+Ly6G Myeloid-derived suppressor cells play a critical role in the resolution of acute inflammation and the subsequent tissue repair process after spinal cord injury (pages 74–88)

      Hirokazu Saiwai, Hiromi Kumamaru, Yasuyuki Ohkawa, Kensuke Kubota, Kazu Kobayakawa, Hisakata Yamada, Takehiko Yokomizo, Yukihide Iwamoto and Seiji Okada

      Article first published online: 15 JAN 2013 | DOI: 10.1111/jnc.12135

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      Myeloid-derived suppressor cells (MDSCs) exert immunosuppressive effects in several inflammatory diseases, including cancer and autoimmune disease. We demonstrated that Ly6C+Ly6G myeloid cells which infiltrated into injured spinal cord had a typical feature of MDSCs and played a critical role in the attenuation of acute inflammation and the subsequent tissue repair process after spinal cord injury (SCI). Our findings clarified the role of MDSCs after traumatic SCI, and suggested a potential MDSC-based therapeutic strategy for the acute phase of central nervous system injury.

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      Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states (pages 89–101)

      Peter Hahl, Taron Davis, Cecilia Washburn, Jack T. Rogers and Ann Smith

      Article first published online: 25 FEB 2013 | DOI: 10.1111/jnc.12165

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      Hemopexin helps protect the brain against heme toxicity from blood released in hemorrhage, ischemia, and stroke. Human neuron models have demonstrated that the hemopexin heme transport system is likely to be an important aspect of heme-iron detoxification, even in inflammatory conditions associated with traumatic injury or the development of neuro-degenerative diseases such as Alzheimer's Disease. Hemopexin provides safe heme sequestration and delivery for breakdown followed by heme oxygenase-1 and amyloid precursor protein induction. This research provides novel mechanistic insights into how hemopexin safely controls brain heme and iron levels, and should help develop therapies to treat diseases in which abnormal metal handling and oxidative stress are implicated in the pathogenesis.

    9. Molecular Basis of Disease

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      Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA (pages 102–110)

      Mariana Angoa-Pérez, Michael J. Kane, Denise I. Briggs, Dina M. Francescutti, Catherine E. Sykes, Mrudang M. Shah, David M. Thomas and Donald M. Kuhn

      Article first published online: 8 JAN 2013 | DOI: 10.1111/jnc.12114

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      Mephedrone is a psychoactive component of ‘bath salts’. Despite its remarkable structural similarity to the neurotoxic amphetamines, mephedrone is not neurotoxic. Mephedrone is often co-abused with amphetamines, and data presented here show that when combined with methamphetamine, amphetamine, or MDMA, mephedrone significantly increases the neurotoxicity of the latter drugs. These findings focus much needed attention on the dangers associated with this designer drug of abuse.

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      Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice (pages 111–124)

      Tomohiro Nakanishi, Masamitsu Shimazawa, Sou Sugitani, Takashi Kudo, Shunsuke Imai, Yuta Inokuchi, Kazuhiro Tsuruma and Hideaki Hara

      Article first published online: 7 JAN 2013 | DOI: 10.1111/jnc.12116

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      In the present study, excessive visible light exposure induced nitric oxide (NO) production, protein aggregation such as S-opsin in endoplasmic reticulum (ER), and expressions of bip and C/EBP-homologous protein (chop) mRNAs in photoreceptors. Knockdown of chop mRNA inhibited photoreceptor cell death induced by light exposure. Our findings suggest that ER stress plays a pivotal role in light-induced photoreceptor degeneration, and that this effect is mediated by CHOP. Therefore, the modulation of ER stress may be a potential therapeutic strategy for the treatment of retinal degenerative diseases.

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      Pharmacological analysis of the cortical neuronal cytoskeletal protective efficacy of the calpain inhibitor SNJ-1945 in a mouse traumatic brain injury model (pages 125–132)

      Mona Bains, John E. Cebak, Lesley K. Gilmer, Colleen C. Barnes, Stephanie N. Thompson, James W. Geddes and Edward D. Hall

      Article first published online: 28 JAN 2013 | DOI: 10.1111/jnc.12118

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      This study details a dose-response and therapeutic window analysis of the brain and cell penetrable calpain inhibitor SNJ-1945 concerning its ability to reduce cortical cytoskeletal degradation when administered during the first minutes and hours after controlled cortical impact traumatic brain injury in the mouse. The compound produced a maximum 60% decrease in cytoskeletal damage when administered within the first hour after TBI, but lost its effect if treatment was delayed for 1 hour. These results fail to support the clinical practicality of direct calpain inhibition as a neuroprotective strategy.

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      Hyperammonemia alters the modulation by different neurosteroids of the glutamate–nitric oxide–cyclic GMP pathway through NMDA- GABAA- or sigma receptors in cerebellum in vivo (pages 133–143)

      Alba González-Usano, Omar Cauli, Ana Agustí and Vicente Felipo

      Article first published online: 17 FEB 2013 | DOI: 10.1111/jnc.12119

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      Several neurosteroids modulate the glutamate–nitric oxide–cGMP pathway in cerebellum through modulation of NMDA- GABAA- or sigma receptors. Hyperammonemia alters neurosteroids' concentrations and impair this pathway, leading to cognitive impairment. We show, by in vivo brain microdialysis, that hyperammonemia modifies the type of effects of pregnanolone and pregnenolone (in red) and potentiates other neurosteroids' effects. This may contribute to cognitive impairment.

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      Important functional role of residue x of the presenilin GxGD protease active site motif for APP substrate cleavage specificity and substrate selectivity of γ-secretase (pages 144–156)

      Benedikt Kretner, Akio Fukumori, Peer-Hendrik Kuhn, Blanca Isabel Pérez-Revuelta, Stefan F. Lichtenthaler, Christian Haass and Harald Steiner

      Article first published online: 15 JAN 2013 | DOI: 10.1111/jnc.12124

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      γ-Secretase substrate recognition and cleavage is an incompletely understood process. Here, we show that residue x of the GxGD active site motif of γ-secretase (L383 in presenilin 1), while representing its functionally least critical residue, contributes to substrate cleavage efficiency and selectivity. Our data substantiate the critical role of the GxGD motif in the catalytic subunit of γ-secretase for substrate selection and/or cleavage efficiency.

      Read the Editorial Highlight for this article on doi: 10.1111/jnc.12077.

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      Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease (pages 157–171)

      Misha Zilberter, Anton Ivanov, Sofya Ziyatdinova, Marat Mukhtarov, Anton Malkov, Alan Alpár, Giuseppe Tortoriello, Catherine H. Botting, Lívia Fülöp, Alex A. Osypov, Asla Pitkänen, Heikki Tanila, Tibor Harkany and Yuri Zilberter

      Article first published online: 10 JAN 2013 | DOI: 10.1111/jnc.12127

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      When Alzheimer's disease is diagnosed, it is too late for any known treatment. Earlier stages are characterized by metabolic crisis and neuronal hyperactivity leading to increased energy demands, thus creating a vicious circle. We show that dietary supplementation with natural energy substrates in Alzheimer's mice model breaks this vicious circle reversing epileptogenesis in vivo and correcting neuronal pathologies ex vivo/in vitro.

      Read the Editorial Highlight for this article on doi: 10.1111/jnc.12138.

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