Omarigliptin Mitigates Lipopolysaccharide-Induced Neuroinflammation and Dysfunction of the Integrity of the Blood–Brain Barrier

Abstract

The blood-brain barrier (BBB) is an important barrier that separates brain tissue from peripheral blood. The permeability of the BBB can be destroyed by external harmful factors, such as lipopolysaccharide (LPS), which contributes to neuroinflammation and central nervous system diseases. The present study aims to investigate the protective effects of Omarigliptin against LPS-induced neuroinflammation and the underlying mechanism using a series of both in vivo and in vitro experiments. A neuroinflammation model was established by intraperitoneal injection of LPS into mice. We found that administration of Omarigliptin reduced LPS-induced inflammatory responses by inhibiting the expressions of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Importantly, we found that Omarigliptin protected the integrity of the BBB against LPS by increasing the expression of the tight junction proteins claudin-1 and claudin-5. Our results also demonstrate that Omarigliptin reduced LPS-induced increase in expressions of matrix matalloproteinases-2 (MMP-2) and matrix matalloproteinases-9 (MMP-9) at both the mRNA and protein levels. Notably, Omarigliptin showed a powerful beneficial effect against LPS-induced cell damage in bEnd.3 brain endothelial cells by reducing the release of high mobility group box chromosomal protein 1 (HMGB-1). Consistently, Omarigliptin ameliorated LPS-induced exacerbation of endothelial permeability by increasing the expressions of claudin-1 and claudin-5 and reducing the expression of MMP-2 and MMP-9. Mechanistically, Omarigliptin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88/nuclear factor κB (TLR4/Myd88/NF-κB) signaling pathway. On the basis of these findings, we concluded that Omarigliptin might mitigate LPS-induced neuroinflammation and dysfunction of the integrity of the blood-brain barrier.

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

“…Metformin ( Takata et al, 2013 ), pitavastatin ( Morofuji et al, 2010 ), siponimod ( Spampinato et al, 2021 ), and cilostazol ( Horai et al, 2013 ) possess the ability to strengthen brain endothelial barrier properties through modulating intracellular signaling in physiological conditions. Minocycline ( Yang et al, 2015 ), alogliptin ( Hao et al, 2019 ), zafirlukast ( Zeng et al, 2020 ), siponimod ( Spampinato et al, 2021 ), memantine ( Zhu et al, 2019 ), cilostazol ( Horai et al, 2013 ; Takeshita et al, 2014 ), candesartan ( So et al, 2015 ), perampanel ( Chen et al, 2021 ), lithium ( Ji et al, 2021 ), omarigliptin ( Du and Wang, 2020 ) and 5′-azacytidine ( Kalani et al, 2014 ) restore the barrier function dependently of specific pathological conditions (e.g., hypoxia, etc.). Ruxolitinib ( Takata et al, 2019 ) inhibits activation of pericytes to release inflammatory mediators, resulting in restoration of the BBB.…”

Blood-Brain Barrier Disruption by Lipopolysaccharide and Sepsis-Associated Encephalopathy

“…Omarigliptin is a novel once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the treatment of type 2 diabetes ( Biftu et al, 2014 ). Studies have found that Omarigliptin can not only maintain the integrity of the BBB by inhibiting neuroinflammation, but also reduce the expression of MMP-2 and MMP-9 to protect TJs protein ( Du and Wang, 2020 ). These results suggest that, for the management of sepsis patients in intensive care unit (ICU), attentions should also be paid to the blood glucose changes and the application of insulin, to reduce the likelihood of SAE ( Huang et al, 2020a ).…”

Piceatannol Protects Brain Endothelial Cell Line (bEnd.3) against Lipopolysaccharide-Induced Inflammation and Oxidative Stress

“…LPS has also been reported to cause oxidative stress by increasing ROS generation [24]. ROS are closely associated with neurological diseases and are a key mediator in promoting inflammatory response and BBB destruction [26]. A number of experimental studies have shown that an excessive increase in ROS reduces the expression of tight junction proteins in endothelial cells, which increases BBB permeability and causes nervous-system-related diseases [27,28].…”