| Autor: |
Gerard Ferrer Esteban, José Marco-Contelles, Ignacio-Andres Romero, Babette B. Weksler, Mercedes Unzeta, Montserrat Solé, Ping Sun, Tsutomu Inokuchi, Pierre-Olivier Couraud |
| Rok vydání: |
2015 |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology. 172:5390-5402 |
| ISSN: |
0007-1188 |
| DOI: |
10.1111/bph.13328 |
| Popis: |
BACKGROUND AND PURPOSE Stroke and Alzheimer's disease (AD) are related pathologies in which the cerebrovascular system is involved. Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), increased in both stroke and AD patients' plasma, contributes to the vascular damage. During inflammation its enzymatic activity mediates leukocyte recruitment into the injured tissue, inducing damage in the blood-brain barrier (BBB) and neuronal tissue. We hypothesized that through the alteration of cerebrovascular function, SSAO/VAP-1 might play a role in the stroke-AD transition. Therefore, the protective effect on the BBB of the novel multitarget-directed ligand (MTDL) DPH-4, initially designed for AD therapy, was evaluated. EXPERIMENTAL APPROACH A human microvascular brain endothelial cell line expressing the human SSAO/VAP-1 (hCMEC/D3 hSSAO/VAP-1) was generated, as SSAO/VAP-1 expression is lost in cultured cells. To simulate ischemic damage, oxygen and glucose deprivation (OGD) and reoxygenation conditions were established in these cells. The protective role of DPH-4 was then evaluated in the presence of methylamine as an SSAO/VAP-1 substrate and/or β-amyloid (Aβ). KEY RESULTS Under these conditions, DPH-4 was able to protect brain endothelial cells from OGD and reoxygenation-induced damage, as well as to decrease SSAO-dependent leukocyte adhesion. DPH-4 was also effective against the damage induced by OGD and reoxygenation in the presence of Aβ as a model of AD pathology. CONCLUSIONS AND IMPLICATIONS These results allow us to conclude that the multitarget compound DPH-4 might provide a therapeutic benefit to delay the onset and/or progression of these two linked neurological pathologies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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