Abstract
This study explores the effect of citicoline on the permeability and expression of tight junction proteins (TJPs) in endothelial cells under hypoxia/aglycemia conditions. Hypoxia or oxygen and glucose deprivation (OGD) was utilized to induce endothelial barrier breakdown model on human umbilical vein endothelial cells (HUVECs) and mouse brain microvascular endothelial cells (bEnd.3s). The effect of citicoline on endothelial barrier breakdown models was determined at either low or high concentrations. FITC-Dextran flux was used to examine the endothelial permeability. The expression of TJPs was measured by immunofluorescence, Real-time PCR and Western Blot methods. Results showed that hypoxia or OGD increased the permeability of HUVECs accompanied with down-regulation of occludens-1 (ZO-1) and occludin at both mRNA and protein levels. Similarly in bEnd.3s, hypoxia increased the permeability and decreased the expression of ZO-1 and claudin-5. Citicoline treatment dose-dependently decreased the permeability in these two models, which paralleled with elevated expression of TJPs. The data demonstrate that citicoline restores the barrier function of endothelial cells compromised by hypoxia/aglycemia probably via up-regulating the expression of TJPs.
Highlights
Citicoline (CDP-choline, cytidine diphosphate choline, cytidine 59-diphosphocholine) is composed of ribose, pyrophosphate, cytosine and choline; clinically, CDP-choline is commonly used for treating various types of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS) and Alzheimer disease (AD) [1]
We demonstrate for the first time that citicoline improves the endothelial barrier function impaired by hypoxia/oxygen and glucose deprivation (OGD) via upregulating the expression of Tight junctions proteins (TJPs)
We used hypoxia and OGD conditions to establish in vitro endothelial barrier breakdown models in these two endothelial cell lines
Summary
Citicoline (CDP-choline, cytidine diphosphate choline, cytidine 59-diphosphocholine) is composed of ribose, pyrophosphate, cytosine and choline; clinically, CDP-choline is commonly used for treating various types of neurodegenerative diseases, such as Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS) and Alzheimer disease (AD) [1]. The pathophysiology of neurodegenerative diseases is complex which includes cholinergic deficit, glutamate excitatory [6], neuroinflammation [7], immunity dysregulation [8], glucose hypometabolism and blood–brain barrier (BBB) disruption [9,10]; the underlying mechanisms of citicoline’s therapeutic effects on neurological diseases are largely unknown. Cerebral vascular endothelial cells develop highly selective barrier which controls the exchanges between blood and brain compartments for the maintenance and regulation of the neuronal microenvironment [13]. Tight junctions proteins (TJPs) such as zonula occludens-1 (ZO-1), occludin and the claudin family exist in cerebral vascular endothelial cells, which are the most crucial factors modulating barrier integrity [14] [15]. It has been suggested that BBB dysfunction in AD is likely related to the injury or dysregulation of TJPs [16]
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