上睑下垂
内质网
氧化应激
神经退行性变
细胞生物学
医学
化学
神经科学
生物
细胞凋亡
内科学
内分泌学
程序性细胞死亡
生物化学
疾病
作者
Xiaolin Zhong,Yajuan Wang,Dandan Liu,Y. T. Liang,Wenjun Liu,Yanmei Huang,Lihua Xie,Wenzhi Cao,Xu Yang,Ling Chen
出处
期刊:Neuroscience
[Elsevier]
日期:2023-05-01
卷期号:517: 117-127
被引量:4
标识
DOI:10.1016/j.neuroscience.2023.02.005
摘要
Sepsis-associated encephalopathy (SAE) is a common neurological complication of sepsis and is characterized by hyperneuroinflammation. NLRP3 inflammasome-mediated pyroptosis can induce an inflammatory cascade response and plays a key role in SAE. TRPV4 is involved in the hyperinflammatory response associated with inflammation; however, whether TRPV4 inhibition might alleviate SAE-related brain damage is still unknown. Therefore, we aimed to investigate the role and mechanism of HC067047, a potent inhibitor of TRPV4, in hyperneuroinflammation and blood-brain barrier (BBB) dysfunction in a lipopolysaccharide (LPS)-induced SAE mouse model. We found that HC067047 administration significantly inhibited the expression of TRPV4 and p-CamkIIα in the hippocampi of SAE mice. Furthermore, HC067047 treatment attenuated LPS-induced endoplasmic reticulum (ER) stress and oxidative stress (OS), thus remarkably preventing NLRP3 inflammasome-mediated pyroptosis, as well as the expression of proinflammatory factors (IL-1β and IL-18). Additionally, we found that HC067047 selectively prevented pyroptosis in hippocampal cells, mainly the neurons, oligodendrocytes and the resident microglia. The disruption of BBB integrity in SAE mice was also rescued by HC067047 intervention. Thus, we can conclude that the TRPV4 inhibitor HC067047 could protect against hippocampal cell pyroptosis, which might be due to the attenuation of the NLRP3 inflammasome-mediated pyroptosis pathway caused by ER stress and OS. Our findings suggest a potential preventive role for HC067047 in SAE.
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