title: Neuroprotective arylpiperazine dopaminergic/serotonergic ligands suppress experimental autoimmune encephalomyelitis in rats.
abstract: Arylpiperazine-based dopaminergic/serotonergic ligands exert neuroprotective activity. We examined the effect of arylpiperazine D2 /5-HT1A ligands, N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl}-phenyl]-picolinamide (6a) and N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), in experimental autoimmune encephalomyelitis (EAE), a model of neuroinflammation. Both compounds (10 mg/kg i.p.) reduced EAE clinical signs in spinal cord homogenate-immunized Dark Agouti rats. Compound 6b was more efficient in delaying the disease onset and reducing the maximal clinical score, which correlated with its higher affinity for D2 and 5-HT1A receptors. The protection was retained if treatment was limited to the effector (from day 8 onwards), but not the induction phase (day 0-7) of EAE. Compound 6b reduced CNS immune infiltration and expression of mRNA encoding the proinflammatory cytokines tumor necrosis factor, IL-6, IL-1, and GM-CSF, TH 1 cytokine IFN-γ, TH 17 cytokine IL-17, as well as the signature transcription factors of TH 1 (T-bet) and TH 17 (RORγt) cells. Arylpiperazine treatment reduced apoptosis and increased the activation of anti-apoptotic mediators Akt and p70S6 kinase in the CNS of EAE animals. The in vitro treatment with 6b protected oligodendrocyte cell line OLN-93 and neuronal cell line PC12 from mitogen-activated normal T cells or myelin basic protein-activated encephalitogenic T cells. In conclusion, arylpiperazine dopaminergic/serotonergic ligands suppress EAE through a direct neuroprotective action and decrease in CNS inflammation. Arylpiperazine dopaminergic/serotonergic ligands reduce neurological symptoms of acute autoimmune encephalomyelitis in rats without affecting the activation of autoreactive immune response, through mechanisms involving a decrease in CNS immune infiltration, as well as direct protection of CNS from immune-mediated damage. These data indicate potential usefulness of arylpiperazine-based compounds in the treatment of neuroinflammatory disorders such as multiple sclerosis.
authors.affiliation: Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Marjan
authors.initials: M
authors.lastname: Popovic
authors.affiliation: Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Stanojevic
authors.affiliation: Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Tosic
authors.affiliation: Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Isakovic
authors.affiliation: Institute of Medical and Clinical Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Verica
authors.initials: V
authors.lastname: Paunovic
authors.affiliation: Galenika AD, Belgrade, Serbia.
authors.forename: Sasa
authors.initials: S
authors.lastname: Petricevic
authors.affiliation: Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Martinovic
authors.affiliation: Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Darko
authors.initials: D
authors.lastname: Ciric
authors.affiliation: Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kravic-Stevovic
authors.affiliation: ORGENTEC GmbH, Mainz, Germany.
authors.forename: Vukic
authors.initials: V
authors.lastname: Soskic
authors.affiliation: ICTM, University of Belgrade, Belgrade, Serbia.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Kostic-Rajacic
authors.affiliation: Division of Surgery & Interventional Science, University College London (UCL), London, UK.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Shakib
authors.affiliation: Institute of Histology and Embryology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bumbasirevic
authors.affiliation: Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D015259:Dopamine Agents; D015850:Interleukin-6; D008024:Ligands; D018696:Neuroprotective Agents; D012701:Serotonin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004298:Dopamine
keywords: CNS inflammation; apoptosis; arylpiperazines; neuroprotection; oligodendrocytes