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Metalloproteinase 9 (MMP-9) is able to degrade collagen Ⅳ,an important component of blood-brain barrier (BBB).Expression of MMPs,especially MMP-9,correlates with BBB disruption during central nervous system inflammation.Propofol has been reported to have anti-inflammation effects.In this study,we investigated the effects of propofol on TNF-α-induced MMP-9 expression in human cerebral microvascular endothelial cells (hCMEC/D3 cells) and explored the underlying mechanisms.The hCMEC/D3 cells were treated with propofol (25 μM),followed by TNF-α (25 ng/mL).We showed that TNF-α treatment markedly increased MMP-9 expression and decreased collagen Ⅳ expression in hCMEC/D3 cells,which was blocked by pretreatment with propofol.TNF-α-induced downregulation of collagen Ⅳ was also reversed by MMP-9 knockdown with siRNA.We revealed that TNF-α upregulated MMP-9 expression in hCMEC/D3 cells through activation of Ca2+/CAMK Ⅱ/ERK/NF-κB signaling pathway;co-treatment with inhibitors of CaMK Ⅱ (KN93),ERK (LY3214996),NF-KB (PDTC) or Ca2+chelator (BAPTA-AM) abrogated the effect of TNF-α on MMP-9 expression.We further established an in vitro BBB model by co-culturing of hCMEC/D3 cells and human astrocytes for 6 days and measuring trans-endothelial electrical resistance (TEER) to reflect the BBB permeability.TNF-α treatment markedly decreased TEER value,which was attenuated by pretreatment with propofol (25 μM) or MMP-9 knockdown with siRNA.In conclusion,propofol inhibits TNF-α-induced MMP-9 expression in hCMEC/D3 cells via repressing the Ca2+/CAMKⅡ/ERK/NF-KB signaling pathway.TNF-α-impaired BBB integrity could be reversed by propofol,and propofol attenuates the inhibitory effect of TNF-α on collagen Ⅳ.