Michael Spedding

Clinical Research Solutions

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Co-Authors

S P H Alexander

University of Nottingham

Adam J Pawson

University of Edinburgh

Joanna L Sharman

Theodore Roosevelt High School

Anthony P. Davenport

University of Cambridge

Elena Faccenda

University of Edinburgh

Anthony J. Harmar

University of Edinburgh

Thérèse M. Jay

Inserm

John A. Peters

Ninewells Hospital

Christine M. Brown

Swinburne University of Technology

Jamie A. Davies

University of Edinburgh

Cooperative Institutions

Inserm

206

Centre National de la Recherche Scientifique

191

Université Paris Cité

113

Servier (France)

Sorbonne Université

Sorbonne Paris Cité

Assistance Publique – Hôpitaux de Paris

Institut des Hautes Études Scientifiques

University of Edinburgh

Egis Pharmaceuticals (Hungary)

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Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

Frontiers in Molecular Neuroscience (2018)

Alexandre Henriques Vincent Croixmarie Alexandra Bouscary Althéa Mosbach Céline Keime

Lipid metabolism is drastically dysregulated in amyotrophic lateral sclerosis and impacts prognosis of patients. Animal models recapitulate alterations in the energy metabolism, including hypermetabolism and severe loss of adipose tissue. To gain insight into the molecular mechanisms underlying disease progression in amyotrophic lateral sclerosis, we have performed RNA-sequencing and lipidomic profiling in spinal cord of symptomatic SOD1G86R mice. Spinal transcriptome of SOD1G86R mice was characterized by differential expression of genes related to immune system, extracellular exosome and lysosome. Hypothesis-driven identification of metabolites showed that lipids, including sphingomyelin(d18:0/26:1), ceramide(d18:1/22:0) and phosphatidylcholine(o-22:1/20:4) showed profound altered levels. A correlation between disease severity and gene expression or metabolite levels was found for sphingosine, ceramide(d18:1/26:0), Sgpp2, Sphk1 and Ugt8a. Joint-analysis revealed a significant enrichment of glycosphingolipid metabolism in SOD1G86R mice, due to the down-regulation of ceramide, glucosylceramide and lactosylceramide and the overexpression of genes involved in their recycling in the lysosome. A drug-gene interaction database was interrogated to identify potential drugs able to modulate the dysregulated genes from the signalling pathway. Our results suggest that complex lipids are pivotally changed during the first phase of motor symptoms in an animal model of amyotrophic lateral sclerosis.

Lactosylceramide

Sphingolipid

10.3389/fnmol.2017.00433

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Citations (57)

Stereospecific blockade of α2-adrenoceptors by (+)-butaclamol: implications for the characterization of dopamine receptors

Journal of Pharmacy and Pharmacology (1982)

Michael Spedding Cyntha van den Berg

Journal Article Stereospecific blockade of α2-adrenoceptors by (+)-butaclamol: implications for the characterization of dopamine receptors Get access M Spedding, M Spedding Centre de Recherche Merrell International, 16, rue d'Ankara, 67084 Strasbourg Cedex, France Search for other works by this author on: Oxford Academic Google Scholar C Berg C Berg Centre de Recherche Merrell International, 16, rue d'Ankara, 67084 Strasbourg Cedex, France Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 34, Issue 1, January 1982, Pages 56–58, https://doi.org/10.1111/j.2042-7158.1982.tb04681.x Published: 12 April 2011 Article history Received: 12 June 1981 Published: 12 April 2011

Stereospecificity

10.1111/j.2042-7158.1982.tb04681.x

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Citations (8)

(Phenylpiperazinyl-butyl)oxindoles as Selective 5-HT₇ Receptor Antagonists

Journal of Medicinal Chemistry (2008)

Balázs Volk József Barkóczy Endre Hegedűs Szabolcs Udvari István Gacsályi

A series of potent 5-hydroxytryptamine 7 (5-HT 7) ligands has been synthesized that contain a 1,3-dihydro-2 H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT 7 and 5-HT 1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT 7 receptor. According to the structure-activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT 7 receptor-ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2 H-indol-2-one ( 9e') exhibited selective 5-HT 7 antagonist activity ( K i = 0.79 nM). The in vivo pharmacological potencies of these 5-HT 7 receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests.

Oxindole

5-HT7 receptor

10.1021/jm070279v

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Citations (91)

A functional correlate for the dihydropyridine binding site in rat brain

Nature (1985)

Derek N. Middlemiss Michael Spedding

Nitrendipine

10.1038/314094a0

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Citations (253)

IUPHAR guidelines for classification of new receptor subtypes

Pharmacological Research (1995)

Pmgr Vanhoutte Michael Spedding

Clinical Pharmacology

10.1016/1043-6618(95)80096-4

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Citations (2)

Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile

Cells (2022)

Michael Spedding C. Sebban Thérèse M. Jay Cyril Rocher B Tesolin‐Decros

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

Phencyclidine

Typical antipsychotic

10.3390/cells11071181

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Citations (2)

Multiple exposures to familiar conspecific withdrawal is a novel robust stress paradigm in ewes

Physiology & Behavior (2011)

Vanessa Guesdon Séverine Ligout Philippe Delagrange Michael Spedding Frédéric Lévy

Social Isolation

Stressor

Anticipation (artificial intelligence)

Social Stress

10.1016/j.physbeh.2011.08.011

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Citations (23)

Drug repositioning in neurodegeneration: An overview of the use of ambroxol in neurodegenerative diseases

European Journal of Pharmacology (2020)

Alexandra Bouscary Cyril Quessada Frédérique René Michael Spedding Alexandre Henriques

Ambroxol

Approved drug

10.1016/j.ejphar.2020.173446

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Citations (13)

Quantification of experimentally induced ischaemic damage to smooth muscle cell membranes within the wall of resistance arteries

Journal of Vascular Research (1991)

C.J. Daly Jonah Gordon J.C. McGrath Michael Spedding

Source

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Citations (0)

IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data

Nucleic Acids Research (2010)

Joanna L Sharman Chidochangu P. Mpamhanga Michael Spedding Pierre Germain Bart Staels

The IUPHAR database is an established online reference resource for several important classes of human drug targets and related proteins. As well as providing recommended nomenclature, the database integrates information on the chemical, genetic, functional and pathophysiological properties of receptors and ion channels, curated and peer-reviewed from the biomedical literature by a network of experts. The database now includes information on 616 gene products from four superfamilies in human and rodent model organisms: G protein-coupled receptors, voltage- and ligand-gated ion channels and, in a recent update, 49 nuclear hormone receptors (NHRs). New data types for NHRs include details on co-regulators, DNA binding motifs, target genes and 3D structures. Other recent developments include curation of the chemical structures of approximately 2000 ligand molecules, providing electronic descriptors, identifiers, link-outs and calculated molecular properties, all available via enhanced ligand pages. The interface now provides intelligent tools for the visualization and exploration of ligand structure-activity relationships and the structural diversity of compounds active at each target. The database is freely available at http://www.iuphar-db.org .

10.1093/nar/gkq1062

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Citations (100)