title: In-vitro and in-vivo evaluation of the modulatory effects of the multitarget compound ASS234 on the monoaminergic system.
abstract: OBJECTIVE
  To evaluate the in-vitro and in-vivo effects on monoaminergic neurotransmission of ASS234, a promising multitarget-directed ligand (MTDL), for Alzheimer's disease (AD) therapy.
  
  
  METHODS
  In vitro was explored the effect of ASS234 on the monoaminergic metabolism in SH-SY5Y and PC12 cell lines, and remaining activity of both monoamine oxidase (MAO) isoforms was assessed. The corresponding dopamine (DA), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline (NA) levels were determined by HPLC-ED. In-vivo experiments were carried out Wistar rats and intracerebral guide cannulas were implanted in the hippocampus and in the prefrontal cortex by sterotaxic coordinates. The day after microdialysis samples were collected and levels of 5-HT, DA and NA were determined by (UHPLC) with electrochemical detector.
  
  
  RESULTS
  ASS234 induced a significant increase in serotonin (5-HT) levels in SH-SY5Y cells. In PC12 cells, ASS234 increased significantly the ratio of dopamine (DA)/(HVA + DOPAC), although no apparent differences in (NA) were observed. By in-vivo microdialysis, ASS234 showed a significant increase in the extracellular levels of 5-HT and NA in hippocampus whereas in the prefrontal cortex, DA and NA also increased significantly.
  
  
  CONCLUSIONS
  This study reveals the ability of ASS234 a MTDL compound, to enhance the monoaminergic neurotransmission supporting its potential use in AD therapy.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Esteban
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis (FASC), Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Jette, Belgium.
authors.forename: Jolien
authors.initials: J
authors.lastname: Van Schoors
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis (FASC), Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Jette, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Van Eeckhaut
authors.affiliation: Laboratory of Medicinal Chemistry (IQOG, CSIC), Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis (FASC), Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Jette, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D016716:PC12 Cells; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; D007211:Indoles; D008024:Ligands; C570530:N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; D010880:Piperidines; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid
keywords: ASS234; Alzheimer's disease; monoaminergic system; monoamines; neurodegeneration