title: A preliminary investigation of phoshodiesterase 7 inhibitor VP3.15 as therapeutic agent for the treatment of experimental autoimmune encephalomyelitis mice.
abstract: cAMP plays a significant role in signal transduction pathways controlling multiple cellular processes such as inflammation and immune regulation. cAMP levels are regulated by a family of phosphodiesterases (PDEs). We have studied the effects of a novel PDE7 inhibitor (PDE7i) treatment on mice with experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS) and compared it with another PDE7i. EAE was induced by immunizing C57BL/6J mice with myelin oligodendrocyte glycoprotein (MOG35-55) peptide. Mice were treated daily either from disease onset or from disease peak with each PDE7i and with fingolimod (used in therapy for MS patients) and disease evolution was followed by clinical symptoms. We examined neuropathology of spinal cord, ex vivo lymphocyte proliferation by [3H]-thymidine incorporation, TNFα by ELISA and cAMP-PDE mRNAs expression by in situ hybridization histochemistry (ISHH) in spinal cord of EAE mice treated with both PDE7 inhibitors. Treatment of EAE mice with the novel PDE7i, VP3.15 showed more efficacy in reducing clinical signs at 10mgkg-1than the other PDE7i, BRL50481 and similar to fingolimod. VP3.15 acts on peripheral lymphocytes inhibiting their proliferation and TNFα secretion in a dose-dependent manner. PDE7i treatment alters the levels of PDE4B and PDE7 mRNA expression in EAE mice spinal cord. Given the interest in the development of new drugs for MS, including PDE7i as anti-inflammatory drugs, it is important to study the role played by PDE7 in neurodegenerative diseases with inflammatory component to better understand the beneficial and detrimental effects of a future therapy.
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, IIBB-CSIC, IDIBAPS, CIBERNED, Barcelona 08036, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Martín-Álvarez
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, IIBB-CSIC, IDIBAPS, CIBERNED, Barcelona 08036, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Paúl-Fernández
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Palomo
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Gil
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Institut d'Investigacions Biomèdiques de Barcelona, IIBB-CSIC, IDIBAPS, CIBERNED, Barcelona 08036, Spain. Electronic address: guadalupe.mengod@iibb.csic.es.
authors.forename: G
authors.initials: G
authors.lastname: Mengod
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C445081:myelin oligodendrocyte glycoprotein (35-55); D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517459:Pde7a protein, mouse; D000068876:Fingolimod Hydrochloride
keywords: EAE; Neuroinflammation; Pharmacological treatments; cAMP; cAMP-PDE