Abstract
The present study was aimed to evaluate the malvidin’s protective effects on damage induced by 30 min bilateral common carotid artery occlusion (BCCAO) and 60 min reperfusion (RE) in rat pial microcirculation. Rat pial microcirculation was observed using fluorescence microscopy through a closed cranial window. Western blotting analysis was performed to investigate the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS) and matrix metalloproteinase 9 (MMP-9) expression. Moreover, MMP-9 activity was evaluated by zymography. Finally, neuronal damage and radical oxygen species (ROS) formation were assessed. In all animals, pial arterioles were classified in five orders of branching according to Strahler’s method. In hypoperfused rats, 30 min BCCAO and 60 min RE caused a decrease in arteriolar diameter, an increase in microvascular leakage and leukocyte adhesion, accompanied by decreased capillary perfusion and red blood cell velocity (VRBC). Moreover, marked neuronal damage and evident ROS generation were detected. Conversely, malvidin administration induced arteriolar dilation in dose-related manner, reducing microvascular leakage as well as leukocyte adhesion. Capillary perfusion and VRBC were protected. Nitric oxide (NO) synthase inhibition significantly attenuated malvidin’s effects on arteriolar diameter. Western blotting analysis revealed an increase in eNOS and p-eNOS expression, while zymography indicated a decrease in MMP-9 activity after malvidin’s administration. Furthermore, malvidin was able to prevent neuronal damage and to decrease ROS generation. In conclusion, malvidin protects rat pial microcirculation against BCCAO/RE injury, preventing blood-brain impairment and neuronal loss. Malvidin’s effects appear to be mediated by eNOS activation and scavenger activity.
Highlights
MATERIALS AND METHODSSeveral studies indicate that pial microvascular changes during hypoperfusion and reperfusion (RE) injury can mimic the alterations in cerebral microcirculation during ischemic insults (Lapi et al, 2008b, 2015)
The results of the present study indicate that 30 min bilateral common carotid artery occlusion (BCCAO) and subsequent 60 min RE caused marked alterations in the rat pial microcirculation, determining blood brain barrier (BBB) disruption and significant neuronal damage
Malvidin prevented, in doserelated manner, pial microvascular alterations, induced by hypoperfusion-RE, causing a significant increase in arteriolar diameter. This effect on arteriolar function was accompanied by prevention of vessel wall integrity, as demonstrated by the significant decrease in permeability, protection of capillary perfusion, as proven by improved Perfused capillary length (PCL), and recovery of capillary red blood cell velocity, preventing marked inflammation
Summary
Several studies indicate that pial microvascular changes during hypoperfusion and reperfusion (RE) injury can mimic the alterations in cerebral microcirculation during ischemic insults (Lapi et al, 2008b, 2015). Haemodinamic changes in pial microvascular network trigger complex mechanisms involving blood brain barrier (BBB) integrity and consequent influence on neurons and astrocytes (Iadecola, 2004; Lapi et al, 2015). BCCAO determines radical oxygen species (ROS)/nitric oxide (NO) imbalance inducing oxidative stress with subsequent reduced arteriolar diameter and venular wall alterations. These changes are accompanied by interstitial edema as indicated by leakage of fluorescent tracers (Lapi et al, 2012, 2015; Mastantuono et al, 2015). Ischemia-activated MMPs could degrade the extracellular matrix, leading to the opening of the BBB (Fujimura et al, 1999; Aoki et al, 2002; Candelario-Jalil et al, 2009)
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