Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways

Molecules

Shui-Long Guo¹  Rui Liu²  Lin-Lin Wang²  Hai-Lun Jiang²  Jun-Xia Zhang²  Jian-Guo Xing³ 

[1] Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China;Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;Key Laboratory of Uighur Medicine of Xinjiang Uygur Autonomous Region, Xinjiang Institute of Materia Medica, Urumqi 830004, China;

关键词: Alzheimer’s disease;    amyloid-β peptides;    cyclooxygenase-2;    cytokine;    fibrillar amyloid-β peptides;    luteolin;    mitogen-activated protein kinases;    nuclear factor κB;    blood-brain barrier;   

DOI  :  10.3390/molecules22030334

来源: DOAJ

【 摘 要 】

Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ1–40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ1–40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ1–40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ1–40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ1–40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ1–40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ1–40-induced injury.

【 授权许可】

Unknown