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Sun, P.; Esteban, G.; Inokuchi, T.; Marco-Contelles, J.; Weksler, B. B.; Romero, I. A.; Couraud, P. O.; Unzeta, M. and Solé, M.
(2015).
DOI: https://doi.org/10.1111/bph.13328
Abstract
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.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)
