Midazolam Inhibits Tumor Necrosis Factor-α–induced Endothelial Activation

Joo, Hee Kyoung; Oh, Sae Cheol; Cho, Eun Jung; Park, Kyoung Sook; Lee, Ji Young; Lee, Eun Ji; Lee, Sang Ki; Kim, Hyo Shin; Park, Jin Bong; Jeon, Byeong Hwa

doi:10.1097/aln.0b013e318190bc69

Cited by 28 publications

(10 citation statements)

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“…It was suggested that benzodiazepines inhibit murine phagocyte oxidative metabolism and production of IL-1, tumor necrosis factor-alpha (TNF-α) and IL-6 19. Several studies have found that midazolam inhibits human neutrophil function and the activation of human umbilical vein endothelial cells induced by TNF-α in vitro 20,21. Kim, et al9 further discovered that midazolam exerted anti-inflammatory action by inhibiting inducible nitric oxide synthase and cyclooxygenase-2 expression, possibly through the suppression of NF-kappaB and p38 mitogen-activated protein kinase activation.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Effects of Propofol and Midazolam on Inflammation and Oxidase Stress in Children with Congenital Heart Disease Undergoing Cardiac Surgery

et al. 2011

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PurposeTo investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery.Materials and MethodsThirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T0), at 2 h after release of the aorta cross-clamp (T3) and at 24 h after operation (T4) to measure interleukin 6 (IL-6), IL-8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T1) and at 10-20 min after the release of the aorta cross-clamp (T2) to detect heme oxygenase-1 (HO-1) expression.ResultsTracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively).ConclusionPropofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery.

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Section: Discussionmentioning

confidence: 99%

Comparison of the Effects of Propofol and Midazolam on Inflammation and Oxidase Stress in Children with Congenital Heart Disease Undergoing Cardiac Surgery

et al. 2011

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“…Specifically, the TSPO is present in the mitochondria coupled to an anion channel, in platelets, lymphocytes, mononuclear cells, endothelium, vascular smooth muscle, mast cells, and also in microglia and neurons. Several in vitro studies have shown that BDZs that bind to the TSPO can affect cellular and immune functions by suppressing cytokine secretion (Taupin et al, 1991; Kim et al, 2006; Joo et al, 2009; Yousefi et al, 2013), modifying cell proliferation, affecting immune cell migration (Ruff et al, 1985) and cellular phagocytic activity (Jin et al, 2013). Immune cells express GABA receptor transcripts and it has been reported GABA treatment decreases the production of pro-inflammatory cytokines in peripheral macrophages (Bhat et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

Ramírez

Niraula

Sheridan

2016

Brain, Behavior, and Immunity

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Objective Psychosocial stress is associated with altered immunity, anxiety, and depression. Repeated social defeat (RSD), a model of social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b+ /Ly6Chi) that traffic to the brain, promoting anxiety-like behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting social avoidant behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: 1) prevent stress-induced peripheral and central inflammatory responses, and 2) block anxiety and social avoidance behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9%NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b+/CD45high) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like behavior in mice exposed to RSD. Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychosocial stress. The reversal of RSD-induced behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.

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“…Plasma concentrations of benzodiazepines that have been used clinically ranged between 0.1 µM and 50 µM [22]. A study also found that in the range of 3-30 µM midazolam suppresses VCAM-1 and monocyte adhesion in the TNF-α activated endothelial cell [23]. Midazolam at concentrations of 5-20 µM as used in the current study significantly inhibited activation and expression of MMP-9 and expression of MMP-1 and MMP-13.…”

Section: Discussionmentioning

confidence: 66%

Inhibitory effect of midazolam on MMP-9, MMP-1 and MMP-13 expression in PMA-stimulated human chondrocytes via recovery of NF-κB signaling

Wang

Huan²,

Hsieh³

et al. 2013

aoms

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IntroductionMidazolam, a benzodiazepine, has a hypnotic effect and is widely used as an intravenous sedative. Past studies have clearly established that midazolam has beneficial effects in attenuating ischemia-reperfusion injury more than other currently used sedative drugs. However, the role of midazolam on chondroprotection via inhibition of matrix metalloproteinases (MMPs) is warrant investigation. The aim of this study was to examine the mechanisms of action of midazolam on MMP expression via nuclear factor κB (NF-κB) signaling in activated chondrosarcoma cells maintained in vitro.Material and methodsChondrocytes, SW1353 cells, were stimulated with phorbol 12-myristate 13-acetate (PMA) in the absence or presence of various concentrations of midazolam (5-20 µM). Release of MMP-9 into the culture media was determined by gelatin zymography. The expressions of MMP-1, MMP-9 and MMP-13, phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinases and degradation of IκB-α were determined by western blotting assay.ResultsMidazolam significantly down-regulated PMA-induced MMP-9 protein expression at concentrations of 5, 10 and 20 µM, the values were 1.95 ±0.09 (p < 0.01), 1.71 ±0.12 (p < 0.01) and 1.35 ±0.20 (p < 0.001), respectively. At concentrations of 5, 10 and 20 µM, it was significantly inhibited the PMA-induced expressions of MMP-1 (2.27 ±0.10, 1.98 ±0.11 and 1.56 ±0.15; p < 0.001) and MMP-13 (0.89 ±0.04, 0.81 ±0.07, and 0.74 ±0.09; p < 0.001), respectively. Midazolam at concentrations of 10 and 20 µM for 15 min significantly reversed the rate of degradation (0.895 ±0.051; p < 0.05 and 0.926 ±0.060; p < 0.01, respectively) of IκB-α in PMA-chondrocyte cells. In addition, this sedative drug inhibited PMA-induced levels of phos-ERK (1.243 ±0.12, 1.108 ±0.16 and 0.903 ±0.19, respectively) and phos-p38 (1.146 ±0.10, 1.063 ±0.13 and 0.946 ±0.18, at concentrations of (5, 10 and 20 µM), respectively.ConclusionsThese results are important for understanding the mechanism of midazolam in inhibiting PMA-induced MMP expression through the signaling pathways of either NF-κB or ERK/p38 MAPKs down-regulation.

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Midazolam Inhibits Tumor Necrosis Factor-α–induced Endothelial Activation

Abstract: These results suggest that midazolam has an inhibitory action on the endothelial activation and that its action is related to the activation of peripheral benzodiazepine receptor localized in mitochondria of the endothelial cells.

Cited by 28 publications

References 25 publications

Comparison of the Effects of Propofol and Midazolam on Inflammation and Oxidase Stress in Children with Congenital Heart Disease Undergoing Cardiac Surgery

Comparison of the Effects of Propofol and Midazolam on Inflammation and Oxidase Stress in Children with Congenital Heart Disease Undergoing Cardiac Surgery

GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations

Inhibitory effect of midazolam on MMP-9, MMP-1 and MMP-13 expression in PMA-stimulated human chondrocytes via recovery of NF-κB signaling

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