The free-radical scavenger, edaravone, augments NO release from vascular cells and platelets after laser-induced, acute endothelial injuryin vivo

Abstract

In vitro and in vivo experimental models have demonstrated that vascular endothelial function is significantly impaired as a result of oxidative stress, mediated by the generation of oxygen-derived free radicals in response to chronic or acute inflammation. In particular, super-oxide () at specific concentrations leads to the impairment of nitric oxide (NO) bioactivity, and it is known that NO plays a fundamental role in the maintenance of vascular homeostasis. The relationship between reactive oxygen species (ROS) and NO release in thrombosis-related endothelial damage in the peripheral microvasculature remains unclear, however. The purpose of the present study was to investigate the effect of the free-radical scavenger, edaravone, on NO synthesis and thrombotic potential in arterioles after exposure to laser irradiation. Highly sensitive electrochemical NO microsensors were positioned in femoral arterioles of mice, and the kinetics of NO release were recorded in response to standardized laser irradiation in vivo. In addition, images of NO release from damaged vascular cells were investigated in a similar rat model using the NO-sensitive dye 4,5-diaminofluorescein diacetate (DAF-2DA). Thrombogenesis was assessed in carotid arterioles by continuous video microscopy using image analysis software. Laser irradiation led to NO release from perturbed endothelial cells and from platelet-rich thrombi. Edaravone had no significant effect on NO release in non-laser treated, intact endothelium compared with placebo. In contrast, edaravone demonstrated a dose-dependent effect on NO release and thrombogenicity. At a concentration of 10.5 mg/kg per h, edaravone promoted a 5-fold increase in NO and a reduction in platelet-rich thrombus volume to 58% of the placebo values. Our data provide direct evidence to confirm that acute endothelial damage in peripheral microvessels initially induces NO release and that the free-radical scavenger, edaravone, augments NO synthesis leading to suppression of platelet thrombus formation.

In Vivo and In Vitro Treatment With Edaravone Promotes Proliferation of Neural Progenitor Cells Generated Following Neuronal Loss in the Mouse Dentate Gyrus

“…Indeed, accumulating evidence suggests that edaravone modulates inflammatory processes, matrix metalloproteinase levels, and nitric oxide production in addition to its free radical-removing effect (34). In particular, a recent report provided direct evidence to confirm that edaravone promotes nitric oxide synthesis/ release following acute endothelial damage in peripheral microvessels, thus indicating it to have a beneficial effect on some neurodegenerative disorders (35). In addition, previous reports of ours indicated that endogenous or exogenous nitric oxide promotes the proliferation of NPCs derived from the embryonic mouse hippocampus (28,36) as well as from the dentate gyrus of the adult mouse (data not shown).…”

Imaging of Structural Changes in Endothelial Cells and Thrombus Formation at the Site of FeCl₃-Induced Injuries in Mice Cremasteric Arteries

“…In clinical els [13][14][15][16][17] . These stimulations are presumed to produce free radicals to injure endothelial cell function [18][19][20] ; however, the detailed physiological mechanism resulting in formation of arterial occlusive thrombi is yet to be clarified.…”

YAMATO Study (Tissue-Type Plasminogen Activator and Edaravone Combination Therapy)

“…18 It is considered that edaravone prevents new thrombus formation by enhancing the expression of endothelial nitric oxide synthase, improving NO release, and inhibiting the expression of selection. 19 An increased NO level leads to vasorelaxation, and downregulation of the selection level suppresses platelet adhesion, platelet aggregation, and leukocyte adhesion. 20 Therefore, it was expected that edaravone would accelerate early recanalization.…”