title: Protective effect of the multitarget compound DPH-4 on human SSAO/VAP-1-expressing hCMEC/D3 cells under oxygen-glucose deprivation conditions: an in vitro experimental model of cerebral ischaemia.
abstract: OBJECTIVE
  Stroke and Alzheimer's disease (AD) are related pathologies in which the cerebrovascular system is involved. Plasma levels of semicarbazide-sensitive amine oxidase/vascular adhesion protein 1 (SSAO/VAP-1, also known as Primary Amine Oxidase -PrAO) are increased in both stroke and AD patients and contribute to the vascular damage. During inflammation, its enzymatic activity mediates leukocyte recruitment to the injured tissue, inducing damage in the blood-brain barrier (BBB) and neuronal tissue. We hypothesized that by altering cerebrovascular function, SSAO/VAP-1 might play a role in the stroke-AD transition. Therefore, we evaluated the protective effect of the novel multitarget-directed ligand DPH-4, initially designed for AD therapy, on the BBB.
  
  
  METHODS
  A human microvascular brain endothelial cell line expressing human SSAO/VAP-1 was generated, as the expression of SSAO/VAP-1 is lost in cultured cells. To simulate ischaemic damage, these cells were subjected to oxygen and glucose deprivation (OGD) and re-oxygenation conditions. The protective role of DPH-4 was then evaluated in the presence of methylamine, an SSAO substrate, and/or β-amyloid (Aβ).
  
  
  RESULTS
  Under our conditions, DPH-4 protected brain endothelial cells from OGD and re-oxygenation-induced damage, and also decreased SSAO-dependent leukocyte adhesion. DPH-4 was also effective at preventing the damage induced by OGD and re-oxygenation in the presence of Aβ as a model of AD pathology.
  
  
  CONCLUSIONS
  From these results, we concluded that the multitarget compound DPH-4 might be of therapeutic benefit to delay the onset and/or progression of the neurological pathologies associated with stroke and AD, which appear to be linked.
authors.affiliation: Institut de Neurociències i Departament de Bioquímica i Biologia Molecular. Edifici M, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Sun
authors.affiliation: Institut de Neurociències i Departament de Bioquímica i Biologia Molecular. Edifici M, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: G
authors.identifier: http://orcid.org/0000-0002-9383-2150
authors.initials: G
authors.lastname: Esteban
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3.1.1 Tsushima-Naka, Kita-ku, Okayama, 700-8530, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inokuchi
authors.affiliation: Instituto de Química Orgánica General (CSIC), 3 Juan de la Cierva, Madrid, 28006, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Weksler
authors.affiliation: Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, UK.
authors.forename: I A
authors.initials: IA
authors.lastname: Romero
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: P O
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Institut de Neurociències i Departament de Bioquímica i Biologia Molecular. Edifici M, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Unzeta
authors.affiliation: Institut de Neurociències i Departament de Bioquímica i Biologia Molecular. Edifici M, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-4240-6562
authors.initials: M
authors.lastname: Solé
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology*; D055806:Microvessels / Q000166:cytology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; C000611755:DPH-4 compound; D006912:Hydroxyquinolines; D018696:Neuroprotective Agents; D010880:Piperidines; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); D005947:Glucose; D010100:Oxygen