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  1. Article: Developing therapeutics for the treatment of multiple sclerosis.

    Virley, David J

    NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics

    2005  Volume 2, Issue 4, Page(s) 638–649

    Abstract: Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for ... ...

    Abstract Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an alpha4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.
    MeSH term(s) Animals ; Clinical Trials as Topic ; Drug Design ; Humans ; Immunosuppressive Agents/therapeutic use ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/immunology
    Chemical Substances Immunosuppressive Agents
    Language English
    Publishing date 2005-09-07
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2205033-4
    ISSN 1545-5351 ; 1545-5343
    ISSN (online) 1545-5351
    ISSN 1545-5343
    DOI 10.1602/neurorx.2.4.638
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Dietary manipulation and caloric restriction in the development of mouse models relevant to neurological diseases.

    Schroeder, Joern E / Richardson, Jill C / Virley, David J

    Biochimica et biophysica acta

    2010  Volume 1802, Issue 10, Page(s) 840–846

    Abstract: Manipulation of diet such as increasing the level of fat or inducing insulin resistance has been shown to exacerbate the pathology in several animal models of neurological disease. Caloric restriction, however, has been demonstrated to extend the life ... ...

    Abstract Manipulation of diet such as increasing the level of fat or inducing insulin resistance has been shown to exacerbate the pathology in several animal models of neurological disease. Caloric restriction, however, has been demonstrated to extend the life span of many organisms. Reduced calorie consumption appears to increase the resistance of neurons to intracellular and extracellular stress and consequently improves the behavioural phenotype in animal models of neurological diseases, such as Alzheimer's disease. We review the evidence from a variety of mouse models that diet is a risk factor that can significantly contribute to the development of neurological diseases.
    MeSH term(s) Animals ; Caloric Restriction ; Diet ; Disease Models, Animal ; Energy Intake ; Humans ; Mice ; Nervous System Diseases/physiopathology
    Language English
    Publishing date 2010-10
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2010.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Identification of an epidermal keratinocyte AMPA glutamate receptor involved in dermatopathies associated with sensory abnormalities.

    Cabañero, David / Irie, Takeshi / Celorrio, Marta / Trousdale, Christopher / Owens, David M / Virley, David / Albrecht, Phillip J / Caterina, Michael J / Rice, Frank L / Morón, Jose A

    Pain reports

    2017  Volume 1, Issue 3

    Abstract: Introduction: Epidermal keratinocytes are increasingly recognized as active participants in the sensory transduction of itch and pain, processes known to involve primary afferent glutamatergic neurons. However the role of keratinocyte glutamate ... ...

    Abstract Introduction: Epidermal keratinocytes are increasingly recognized as active participants in the sensory transduction of itch and pain, processes known to involve primary afferent glutamatergic neurons. However the role of keratinocyte glutamate signaling in sensory functioning is not fully understood. Here, we present the observation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid type glutamate receptors (AMPAR) in epidermal keratinocytes.
    Methods: Immunohistochemical and
    Results: We found prominent immunolabeling (IL) for the GluA4 subunit of AMPAR in keratinocytes of glabrous and hairy skin of mouse epidermis, as well as in human epidermal keratinocytes. RTPCR confirmed
    Conclusions: We provide evidence that GluA4-containing AMPAR are expressed in epidermal keratinocytes, that human pruritic and painful dermatopathologies have alterations in the keratinocyte expression levels of GluA4-containing AMPAR, and that itch and pain producing substances can directly regulate their production in keratinocytes.
    Language English
    Publishing date 2017-02-08
    Publishing country United States
    Document type Journal Article
    ISSN 2471-2531
    ISSN 2471-2531
    DOI 10.1097/PR9.0000000000000573
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Book: Stroke genomics

    Read, Simon J / Virley, David

    methods and reviews

    (Methods in molecular medicine, ; 104)

    2005  

    Author's details edited by Simon J. Read, David Virley
    Series title Methods in molecular medicine, ; 104
    MeSH term(s) Stroke/genetics
    Language English
    Size x, 351 p. :, ill.
    Publisher Humana Press
    Publishing place Totowa, N.J
    Document type Book
    ISBN 9781588293336 ; 1588293335 ; 9781592598366 ; 1592598366
    Database Catalogue of the US National Library of Medicine (NLM)

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  5. Article: 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease.

    Upton, Neil / Chuang, Tsu Tshen / Hunter, Ann J / Virley, David J

    Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

    2008  Volume 5, Issue 3, Page(s) 458–469

    Abstract: Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of ... ...

    Abstract Alzheimer's disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive performance accompanied by behavioral and psychological syndromes, such as depression and psychosis. The neurochemical correlates of these clinical manifestations now appear to involve dysfunctions of multiple neurotransmitter pathways. Because of the extensive serotonergic denervation that has been observed in the AD brain and the important role played by serotonin (5-HT) in both cognition and behavioral control, this neurotransmitter system has become a focus of concerted research efforts to identify new treatments for AD. 5-HT exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes. One of the newest members of this family is the 5-HT6 receptor, a subtype localized almost exclusively in the CNS, predominating in brain regions associated with cognition and behavior. With the subsequent development of selective 5-HT6 receptor antagonists, preclinical studies in rodents and primates have elucidated the function of this receptor subtype in more detail. It is increasingly clear that blockade of 5-HT6 receptors leads to an improvement of cognitive performance in a wide variety of learning and memory paradigms and also results in anxiolytic and antidepressant-like activity. These actions are largely underpinned by enhancements of cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission, together with learning-associated neuronal remodeling. A preliminary report that the cognitive enhancing properties of a 5-HT6 receptor antagonist (namely, SB-742457) extends into AD sufferers further highlights the therapeutic promise of this mechanistic approach.
    MeSH term(s) Alzheimer Disease/complications ; Alzheimer Disease/drug therapy ; Animals ; Cognition Disorders/drug therapy ; Cognition Disorders/etiology ; Humans ; Receptors, Serotonin/physiology ; Serotonin Antagonists/therapeutic use
    Chemical Substances Receptors, Serotonin ; Serotonin Antagonists ; serotonin 6 receptor
    Language English
    Publishing date 2008-07-02
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2316693-9
    ISSN 1878-7479 ; 1933-7213
    ISSN (online) 1878-7479
    ISSN 1933-7213
    DOI 10.1016/j.nurt.2008.05.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus.

    Ondrejcak, Tomas / Wang, Qinwen / Kew, James N C / Virley, David J / Upton, Neil / Anwyl, Roger / Rowan, Michael J

    European journal of pharmacology

    2012  Volume 677, Issue 1-3, Page(s) 63–70

    Abstract: Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal ... ...

    Abstract Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist "compound A" ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1-42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.
    MeSH term(s) Allosteric Regulation/drug effects ; Amyloid beta-Peptides/pharmacology ; Animals ; Drug Interactions ; Hippocampus/cytology ; Hippocampus/drug effects ; Hippocampus/physiology ; In Vitro Techniques ; Long-Term Potentiation/drug effects ; Male ; Nicotinic Agonists/pharmacology ; Peptide Fragments/pharmacology ; Rats ; Rats, Wistar ; Receptors, Nicotinic/metabolism ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Synaptic Transmission/drug effects ; Thiophenes/chemistry ; Thiophenes/pharmacology ; alpha7 Nicotinic Acetylcholine Receptor
    Chemical Substances Amyloid beta-Peptides ; Chrna7 protein, rat ; Nicotinic Agonists ; Peptide Fragments ; Receptors, Nicotinic ; Sulfonamides ; Thiophenes ; alpha7 Nicotinic Acetylcholine Receptor ; amyloid beta-protein (1-42)
    Language English
    Publishing date 2012-02-29
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2011.12.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Effects of the selective 5-HT(7) receptor antagonist SB-269970 in animal models of psychosis and cognition.

    Waters, Kerry A / Stean, Tania O / Hammond, Beverley / Virley, David J / Upton, Neil / Kew, James N C / Hussain, Ishrut

    Behavioural brain research

    2012  Volume 228, Issue 1, Page(s) 211–218

    Abstract: The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have ... ...

    Abstract The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
    MeSH term(s) Amphetamine/antagonists & inhibitors ; Amphetamine/pharmacology ; Animals ; Animals, Outbred Strains ; Cognition/drug effects ; Disease Models, Animal ; Fluorobenzenes/pharmacology ; Fluorobenzenes/therapeutic use ; Locomotion/drug effects ; Male ; Phencyclidine/antagonists & inhibitors ; Phencyclidine/pharmacology ; Phenols/pharmacokinetics ; Phenols/pharmacology ; Phenols/therapeutic use ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Psychotic Disorders/drug therapy ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin/drug effects ; Recognition (Psychology)/drug effects ; Serotonin Antagonists/pharmacokinetics ; Serotonin Antagonists/pharmacology ; Serotonin Antagonists/therapeutic use ; Sulfonamides/pharmacokinetics ; Sulfonamides/pharmacology ; Sulfonamides/therapeutic use
    Chemical Substances 5-HT(7) receptor, rat ; Fluorobenzenes ; Phenols ; Piperidines ; Receptors, Serotonin ; SB 269970 ; Serotonin Antagonists ; Sulfonamides ; Amphetamine (CK833KGX7E) ; volinanserin (EW71EE171J) ; Phencyclidine (J1DOI7UV76)
    Language English
    Publishing date 2012-03-01
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 449927-x
    ISSN 1872-7549 ; 0166-4328
    ISSN (online) 1872-7549
    ISSN 0166-4328
    DOI 10.1016/j.bbr.2011.12.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457.

    Callaghan, Charlotte K / Hok, Vincent / Della-Chiesa, Andrea / Virley, David J / Upton, Neil / O'Mara, Shane M

    Neuropharmacology

    2012  Volume 63, Issue 5, Page(s) 890–897

    Abstract: Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system ... ...

    Abstract Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.
    MeSH term(s) Aging ; Animals ; Behavior, Animal/drug effects ; Brain/drug effects ; Brain/metabolism ; Cognition/drug effects ; Cognition Disorders/drug therapy ; Cognition Disorders/metabolism ; Male ; Memory, Short-Term/drug effects ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/metabolism ; Neuronal Plasticity/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Nootropic Agents/administration & dosage ; Nootropic Agents/therapeutic use ; Quinolines/administration & dosage ; Quinolines/therapeutic use ; Rats ; Rats, Wistar ; Receptors, Serotonin/chemistry ; Receptors, Serotonin/metabolism ; Serotonin Antagonists/administration & dosage ; Serotonin Antagonists/therapeutic use ; Sulfones/administration & dosage ; Sulfones/therapeutic use ; Synaptic Transmission/drug effects ; Task Performance and Analysis ; Time Factors
    Chemical Substances 3-benzenesulfonyl-8-piperazin-1-ylquinoline ; Nerve Tissue Proteins ; Nootropic Agents ; Quinolines ; Receptors, Serotonin ; Serotonin Antagonists ; Sulfones ; serotonin 6 receptor
    Language English
    Publishing date 2012-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2012.06.034
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: The thiazolidinedione pioglitazone increases cholesterol biosynthetic gene expression in primary cortical neurons by a PPARgamma-independent mechanism.

    Cocks, Graham / Wilde, Jonathan I / Graham, Simon J / Bousgouni, Vicky / Virley, David / Lovestone, Simon / Richardson, Jill

    Journal of Alzheimer's disease : JAD

    2010  Volume 19, Issue 2, Page(s) 631–646

    Abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor ...

    Abstract In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARgamma agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARgamma antagonist GW9662 did not significantly reduce these effects, suggesting a PPARgamma-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease.
    MeSH term(s) Animals ; Cells, Cultured ; Cerebral Cortex/cytology ; Cholesterol/biosynthesis ; Cholesterol/genetics ; Embryo, Mammalian ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling/methods ; Hypoglycemic Agents/pharmacology ; Neurons/drug effects ; Oligonucleotide Array Sequence Analysis/methods ; PPAR gamma/antagonists & inhibitors ; Rats ; Rats, Sprague-Dawley ; Sterol Regulatory Element Binding Protein 1/genetics ; Sterol Regulatory Element Binding Protein 1/metabolism ; Thiazolidinediones/pharmacology ; Time Factors ; Up-Regulation/drug effects
    Chemical Substances Enzyme Inhibitors ; Hypoglycemic Agents ; PPAR gamma ; Srebf1 protein, rat ; Sterol Regulatory Element Binding Protein 1 ; Thiazolidinediones ; Cholesterol (97C5T2UQ7J) ; pioglitazone (X4OV71U42S)
    Language English
    Publishing date 2010
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-2010-1266
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Activation of α7 nicotinic acetylcholine receptors persistently enhances hippocampal synaptic transmission and prevents Aß-mediated inhibition of LTP in the rat hippocampus

    Ondrejcak, Tomas / Wang, Qinwen / Kew, James N.C / Virley, David J / Upton, Neil / Anwyl, Roger / Rowan, Michael J

    European journal of pharmacology. 2012 Feb. 29, v. 677, no. 1-3

    2012  

    Abstract: Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal ... ...

    Abstract Nicotinic acetylcholine receptors mediate fast cholinergic modulation of glutamatergic transmission and synaptic plasticity. Here we investigated the effects of subtype selective activation of the α7 nicotinic acetylcholine receptors on hippocampal transmission and the inhibition of synaptic long-term potentiation by the Alzheimer's disease associated amyloid ß-protein (Aß). The α7 nicotinic acetylcholine receptor agonist “compound A” ((R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl))thiophene-2-carboxamide) induced a rapid-onset persistent enhancement of synaptic transmission in the dentate gyrus in vitro. Consistent with a requirement for activation of α7 nicotinic acetylcholine receptors, the type II α7-selective positive allosteric modulator PheTQS ((3aR, 4S, 9bS)-4-(4-methylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide) potentiated, and the antagonist methyllycaconitine (MLA) prevented the persistent enhancement. Systemic injection of the agonist also induced a similar MLA-sensitive persistent enhancement of synaptic transmission in the CA1 area in vivo. Remarkably, although compound A did not affect control long-term potentiation (LTP) in vitro, it prevented the inhibition of LTP by Aß1–42 and this effect was inhibited by MLA. These findings strongly indicate that activation of α7 nicotinic acetylcholine receptors is sufficient to persistently enhance hippocampal synaptic transmission and to overcome the inhibition of LTP by Aß.
    Keywords Alzheimer disease ; acetylcholine ; agonists ; amyloid ; antagonists ; cholinergic receptors ; hippocampus ; rats ; synaptic transmission
    Language English
    Dates of publication 2012-0229
    Size p. 63-70.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2011.12.008
    Database NAL-Catalogue (AGRICOLA)

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