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  1. Article ; Online: NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury.

    Cook, Denise R / Gleichman, Amy J / Cross, Stephanie A / Doshi, Shachee / Ho, Wenzhe / Jordan-Sciutto, Kelly L / Lynch, David R / Kolson, Dennis L

    Journal of neurochemistry

    2011  Volume 118, Issue 6, Page(s) 1113–1123

    Abstract: Excitotoxic neuronal damage via over-activation of the NMDA receptor has been implicated in many neurodegenerative diseases. In vitro modeling of excitotoxic injury has shown that activation of G-protein coupled receptors (GPCRs) counteracts such injury ... ...

    Abstract Excitotoxic neuronal damage via over-activation of the NMDA receptor has been implicated in many neurodegenerative diseases. In vitro modeling of excitotoxic injury has shown that activation of G-protein coupled receptors (GPCRs) counteracts such injury through modulation of neuronal pro-survival pathways and/or NMDA receptor signaling. We have previously demonstrated that the GPCR APJ and its endogenous neuropeptide ligand apelin can protect neurons against excitotoxicity, but the mechanism(s) of this neuroprotection remain incompletely understood. We hypothesized that apelin can promote neuronal survival by activating pro-survival signaling as well as inhibiting NMDA receptor-mediated excitotoxic signaling cascades. Our results demonstrate that (i) apelin activates pro-survival signaling via inositol trisphosphate (IP(3) ), protein kinase C (PKC), mitogen-activated protein kinase kinase 1/2 (MEK1/2), and extracellular signal-regulated kinase-1/2 (ERK1/2) to protect against excitotoxicity, and (ii) apelin inhibits excitotoxic signaling by attenuating NMDA receptor and calpain activity, and by modulating NMDA receptor subunit NR2B phosphorylation at serine 1480. These studies delineate a novel apelinergic signaling pathway that concurrently promotes survival and limits NMDA receptor-mediated injury to protect neurons against excitotoxicity. Defining apelin-mediated neuroprotection advances our understanding of neuroprotective pathways and will potentially improve our ability to develop therapeutics for excitotoxicity-associated neurodegenerative disorders.
    MeSH term(s) Animals ; Apelin ; Blotting, Western ; Brain/cytology ; Calcium/metabolism ; Calpain/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Electrophysiological Phenomena ; HIV Infections/pathology ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology ; Ion Channels/drug effects ; Ion Channels/physiology ; Macrophages/drug effects ; Neurons/drug effects ; Neuroprotective Agents ; Neurotoxins/toxicity ; Patch-Clamp Techniques ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/drug effects ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism ; Signal Transduction/drug effects ; Transfection
    Chemical Substances APLN protein, human ; Apelin ; Intercellular Signaling Peptides and Proteins ; Ion Channels ; NR2B NMDA receptor ; Neuroprotective Agents ; Neurotoxins ; Receptors, N-Methyl-D-Aspartate ; Calpain (EC 3.4.22.-) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2011-08-08
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/j.1471-4159.2011.07383.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders.

    Gill, Alexander J / Kovacsics, Colleen E / Cross, Stephanie A / Vance, Patricia J / Kolson, Lorraine L / Jordan-Sciutto, Kelly L / Gelman, Benjamin B / Kolson, Dennis L

    The Journal of clinical investigation

    2014  Volume 124, Issue 10, Page(s) 4459–4472

    Abstract: Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV- ... ...

    Abstract Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.
    MeSH term(s) Adult ; Aged ; Antioxidants/metabolism ; Astrocytes/metabolism ; Brain/metabolism ; Central Nervous System ; Cognition Disorders/complications ; Cognition Disorders/virology ; Cohort Studies ; Dimethyl Fumarate ; Female ; Fumarates/chemistry ; HIV Infections/metabolism ; HIV Infections/physiopathology ; HIV-1 ; Heme Oxygenase-1/deficiency ; Heme Oxygenase-1/physiology ; Humans ; Inflammation ; Linear Models ; Macrophages/metabolism ; Macrophages/virology ; Male ; Microglia/metabolism ; Middle Aged ; Nervous System Diseases/metabolism ; Nervous System Diseases/physiopathology ; Oxidative Stress ; Prefrontal Cortex/pathology ; RNA, Small Interfering/metabolism ; Virus Replication
    Chemical Substances Antioxidants ; Fumarates ; RNA, Small Interfering ; HMOX1 protein, human (EC 1.14.14.18) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Dimethyl Fumarate (FO2303MNI2)
    Language English
    Publishing date 2014-09-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI72279
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Dimethyl fumarate, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and macrophage-mediated neurotoxicity: a novel candidate for HIV neuroprotection.

    Cross, Stephanie A / Cook, Denise R / Chi, Anthony W S / Vance, Patricia J / Kolson, Lorraine L / Wong, Bethany J / Jordan-Sciutto, Kelly L / Kolson, Dennis L

    Journal of immunology (Baltimore, Md. : 1950)

    2011  Volume 187, Issue 10, Page(s) 5015–5025

    Abstract: Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, inflammation and immune ... ...

    Abstract Despite antiretroviral therapy (ART), HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation and neurotoxin release from infected and/or activated macrophages/microglia. Furthermore, inflammation and immune activation within both the CNS and periphery correlate with disease progression and morbidity in ART-treated individuals. Accordingly, drugs targeting these pathological processes in the CNS and systemic compartments are needed for effective, adjunctive therapy. Using our in vitro model of HIV-mediated neurotoxicity, in which HIV-infected monocyte-derived macrophages release excitatory neurotoxins, we show that HIV infection dysregulates the macrophage antioxidant response and reduces levels of heme oxygenase-1 (HO-1). Furthermore, restoration of HO-1 expression in HIV-infected monocyte-derived macrophages reduces neurotoxin release without altering HIV replication. Given these novel observations, we have identified dimethyl fumarate (DMF), used to treat psoriasis and showing promising results in clinical trials for multiple sclerosis, as a potential neuroprotectant and HIV disease-modifying agent. DMF, an immune modulator and inducer of the antioxidant response, suppresses HIV replication and neurotoxin release. Two distinct mechanisms are proposed: inhibition of NF-κB nuclear translocation and signaling, which could contribute to the suppression of HIV replication, and induction of HO-1, which is associated with decreased neurotoxin release. Finally, we found that DMF attenuates CCL2-induced monocyte chemotaxis, suggesting that DMF could decrease recruitment of activated monocytes to the CNS in response to inflammatory mediators. We propose that dysregulation of the antioxidant response during HIV infection drives macrophage-mediated neurotoxicity and that DMF could serve as an adjunctive neuroprotectant and HIV disease modifier in ART-treated individuals.
    MeSH term(s) Active Transport, Cell Nucleus/drug effects ; Active Transport, Cell Nucleus/immunology ; Animals ; Anti-HIV Agents/pharmacology ; Antioxidants/metabolism ; Antioxidants/physiology ; Cell Survival/drug effects ; Cell Survival/immunology ; Cells, Cultured ; Cerebral Cortex/drug effects ; Cerebral Cortex/immunology ; Cerebral Cortex/pathology ; Dimethyl Fumarate ; Fumarates/pharmacology ; HIV-1/drug effects ; HIV-1/immunology ; Humans ; Immunosuppressive Agents/pharmacology ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/immunology ; Monocytes/drug effects ; Monocytes/immunology ; Monocytes/pathology ; Neurons/drug effects ; Neurons/pathology ; Neurons/virology ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Virus Replication/drug effects ; Virus Replication/immunology
    Chemical Substances Anti-HIV Agents ; Antioxidants ; Fumarates ; Immunosuppressive Agents ; Neuroprotective Agents ; Dimethyl Fumarate (FO2303MNI2)
    Language English
    Publishing date 2011-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1101868
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The role of cuticular pheromones in courtship conditioning of Drosophila males.

    Siwicki, Kathleen K / Riccio, Paul / Ladewski, Lisa / Marcillac, Fabrice / Dartevelle, Laurence / Cross, Stephanie A / Ferveur, Jean-François

    Learning & memory (Cold Spring Harbor, N.Y.)

    2005  Volume 12, Issue 6, Page(s) 636–645

    Abstract: Courtship conditioning is an associative learning paradigm in Drosophila melanogaster, wherein male courtship behavior is modified by experience with unreceptive, previously mated females. While the training experience with mated females involves ... ...

    Abstract Courtship conditioning is an associative learning paradigm in Drosophila melanogaster, wherein male courtship behavior is modified by experience with unreceptive, previously mated females. While the training experience with mated females involves multiple sensory and behavioral interactions, we hypothesized that female cuticular hydrocarbons function as a specific chemosensory conditioned stimulus in this learning paradigm. The effects of training with mated females were determined in courtship tests with either wild-type virgin females as courtship targets, or with target flies of different genotypes that express distinct cuticular hydrocarbon (CH) profiles. Results of tests with female targets that lacked the normal CH profile, and with male targets that expressed typically female CH profiles, indicated that components of this CH profile are both necessary and sufficient cues to elicit the effects of conditioning. Results with additional targets indicated that the female-specific 7,11-dienes, which induce naive males to court, are not essential components of the conditioned stimulus. Rather, the learned response was significantly correlated with the levels of 9-pentacosene (9-P), a compound found in both males and females of many Drosophila strains and species. Adding 9-P to target flies showed that it stimulates courting males to attempt to copulate, and confirmed its role as a component of the conditioned stimulus by demonstrating dose-dependent increases in the expression of the learned response. Thus, 9-P can contribute significantly to the conditioned suppression of male courtship toward targets that express this pheromone.
    MeSH term(s) Alkenes/pharmacology ; Animals ; Association Learning/drug effects ; Association Learning/physiology ; Chemoreceptor Cells/physiology ; Conditioning, Classical/drug effects ; Conditioning, Classical/physiology ; Courtship ; Drosophila melanogaster/physiology ; Female ; Insect Proteins/physiology ; Male ; Pheromones/pharmacology ; Pheromones/physiology ; Sexual Behavior, Animal/drug effects ; Sexual Behavior, Animal/physiology
    Chemical Substances 9-pentacosene ; Alkenes ; Insect Proteins ; Pheromones ; cuticle proteins, insects
    Language English
    Publishing date 2005-11-14
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1204777-6
    ISSN 1549-5485 ; 1072-0502
    ISSN (online) 1549-5485
    ISSN 1072-0502
    DOI 10.1101/lm.85605
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4107: Show issues Location:
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  5. Article ; Online: Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.

    Akay, Cagla / Cooper, Michael / Odeleye, Akinleye / Jensen, Brigid K / White, Michael G / Vassoler, Fair / Gannon, Patrick J / Mankowski, Joseph / Dorsey, Jamie L / Buch, Alison M / Cross, Stephanie A / Cook, Denise R / Peña, Michelle-Marie / Andersen, Emily S / Christofidou-Solomidou, Melpo / Lindl, Kathryn A / Zink, M Christine / Clements, Janice / Pierce, R Christopher /
    Kolson, Dennis L / Jordan-Sciutto, Kelly L

    Journal of neurovirology

    2014  Volume 20, Issue 1, Page(s) 39–53

    Abstract: HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy ( ... ...

    Abstract HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.
    MeSH term(s) AIDS Dementia Complex/pathology ; Animals ; Anti-Retroviral Agents/toxicity ; Blotting, Western ; Brain/drug effects ; Brain/pathology ; Brain/virology ; Cell Death/drug effects ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Female ; Fluorescent Antibody Technique ; Macaca ; Male ; Neurons/drug effects ; Neurons/pathology ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction
    Chemical Substances Anti-Retroviral Agents ; Reactive Oxygen Species
    Language English
    Publishing date 2014-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1283265-0
    ISSN 1538-2443 ; 1355-0284
    ISSN (online) 1538-2443
    ISSN 1355-0284
    DOI 10.1007/s13365-013-0227-1
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