Propofol attenuated TNF-α-modulated occludin expression by inhibiting Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway in hCMEC/D3 cells

Abstract

Background: The levels of tight junction proteins (TJs), especially occludin, correlate with blood-brain barrier (BBB) disruption caused by inflammation in central nervous system (CNS). It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of tumor necrosis factor-α (TNF-α) and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms. Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK, p38MAPK and occludin were measured by Western blot analysis. The cell viability of hCMEC/D3 cells was measured by cell counting kit-8. Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. TNF-α induced the phosphorylation of p38MAPK, while propofol had no effect on it. In addition, the inhibitors of Hif-1α, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression. Conclusion: TNF-α could decrease the expression of occludin via activating Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway, which was attenuated by propofol.

Calpain‐2 plays a pivotal role in the inhibitory effects of propofol against TNF‐α‐induced autophagy in mouse hippocampal neurons

“…Neuroinflammation has been considered as a major pathogenesis of POCD, through exerting noxious effects on neurons, synapsis and BBB 3‐5 . Previous studies have revealed that pro‐inflammatory cytokine TNF‐α may induce dopaminergic neuron apoptosis, deteriorate brain microglia and astrocyte function, modulate synaptic plasticity and impair neuronal tight junction as well BBB integrity 9‐13,30 . Hippocampal neurons play important roles in learning and memory, and excessive hippocampal neuron autophagy was revealed to be extensively involved in the development of POCD 15,31 .…”

Colibactin in avian pathogenic Escherichia coli contributes to the development of meningitis in a mouse model

“…TNF-α and IL-1β activate the p38/ERK1/2 pathway and increase myosin light chain kinase [ 59 ]. TNF-α also activates the Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway to decrease the expression of occludin in human cerebral microvascular endothelial cell lines [ 60 ]. IL-6 is a pleiotropic cytokine with both proinflammatory and anti-inflammatory effects.…”

Baseline Values and Kinetics of IL-6, Procalcitonin, and TNF-α in Landrace-Large White Swine Anesthetized with Propofol-Based Total Intravenous Anesthesia

“…In addition, the increased inflammatory response and TNF- α levels may exacerbate brain injury, inhibit stimulation of neurogenesis, and cause neuroinflammation and blood-brain barrier disruption [ 3 ]. Also, TNF- α has a physiological role in synaptic transmission and plasticity in the healthy central nervous system, but increased TNF- α levels have an inhibitory effect on glutamate transporters, resulting in increased glutamate concentration and excessive toxicity [ 35 ]. The expression of mTNF- α (a precursor of TNF- α ) in microglia cells increases during propofol anesthesia and may mediate propofol-induced neurotoxicity and cognitive impairment in surgical or critically ill patients [ 31 ].…”