P Sun1, G Esteban1, T Inokuchi2, J Marco-Contelles3, B B Weksler4, I A Romero5, P O Couraud6, M Unzeta1, M Solé1. 1. Institut de Neurociències i Departament de Bioquímica i Biologia Molecular. Edifici M, Facultat de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. 2. 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. 3. Instituto de Química Orgánica General (CSIC), 3 Juan de la Cierva, Madrid, 28006, Spain. 4. Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY, 10065, USA. 5. Department of Life, Health and Chemical Sciences, Open University, Milton Keynes, UK. 6. Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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). KEY 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 AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: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 ADpatients 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. EXPERIMENTAL APPROACH: A human microvascular brain endothelial cell line expressing humanSSAO/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). KEY 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 AND IMPLICATIONS: 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: Adam J Pawson; Joanna L Sharman; Helen E Benson; Elena Faccenda; Stephen P H Alexander; O Peter Buneman; Anthony P Davenport; John C McGrath; John A Peters; Christopher Southan; Michael Spedding; Wenyuan Yu; Anthony J Harmar Journal: Nucleic Acids Res Date: 2013-11-14 Impact factor: 16.971
Authors: Ping Sun; Fan Bu; Jia-Wei Min; Yashasvee Munshi; Matthew D Howe; Lin Liu; Edward C Koellhoffer; Li Qi; Louise D McCullough; Jun Li Journal: Eur J Neurosci Date: 2018-11-29 Impact factor: 3.386
Authors: Giuseppe Di Giovanni; Dubravka Svob Strac; Montse Sole; Mercedes Unzeta; Keith F Tipton; Dorotea Mück-Šeler; Irene Bolea; Laura Della Corte; Matea Nikolac Perkovic; Nela Pivac; Ilse J Smolders; Anna Stasiak; Wieslawa A Fogel; Philippe De Deurwaerdère Journal: Front Neurosci Date: 2016-11-24 Impact factor: 4.677