Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer

Mojumdar, Enamul Haque; Lyubartsev, Alexander P.

doi:10.1016/j.bpc.2010.10.001

Cited by 74 publications

(53 citation statements)

References 55 publications

(93 reference statements)

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“…52 In addition, it has been shown that amide-linked local anesthetics alter membrane fluidity as well as conformation of membrane proteins. 53,54 Thus, on the basis of the results of the current study, we speculate that inhibition of p85 recruitment might be due to alteration in the conformation of TNF-R1 or attenuation of its ability to oligomerize to initiate signaling across the membrane. 51 …”

Section: Discussionmentioning

confidence: 65%

Endothelial Barrier Protection by Local Anesthetics

et al. 2014

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Background Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase–Akt–nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability. Methods Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed. Results Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10−10 M for ropivacaine; IC50 = 5.864 × 10−10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10−10 M for ropivacaine; IC50 = 6.377 × 10−10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated. Conclusions Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory “side-effect” of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease.

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Section: Discussionmentioning

confidence: 65%

Endothelial Barrier Protection by Local Anesthetics

et al. 2014

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“…Presence of ions and charged species like anesthetics and other drugs affects this electrostatic potential significantly, by changing the dipolar orientation of lipid molecules [15]. It has been shown that local anesthetic articaine causes increase of dipole electrostatic potential in the membrane interior [16].…”

Section: Introductionmentioning

confidence: 99%

Effect of head group orientation on phospholipid assembly

Paul

Saha

2017

Phys. Rev. E

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We report the effect of lipid head-group dipole orientation on phase behaviour of phospholipid assembly.The work explains molecular-scale mechanism of ion-lipid, anesthetic-lipid interactions where reorientation of dipoles play important role in membrane potential modification. Molecular Dynamics simulations are performed to analyse structure-property relationship and dynamical behaviour of lipid biomembranes considering coarse-grained model interactions.

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“…This may be due to different localisation site of these two drugs: cimetidine tends to reside at the polar region of bilayer, while paclitaxel tends to stay and aggregate in the hydrophobic region. The ordering effect has been observed in the studies on addition of neutral articaine molecules in DMPC lipids, [28] addition of cholesterol to membranes [30] and addition of lidocaine to DMPC lipids. [31] Figure 5 shows two free energy profiles of cimetidine: one in POPC bilayer without cimetidine (referred as low concentration model) and the other in POPC bilayer with 8 mol % cimetidine molecules (referred as high concentration model).…”

Section: Order Parametermentioning

confidence: 93%

“…The increased APL values have also been observed in articaine-DMPC system. [28] The membrane thickness was calculated using MEMBPLUGIN [29], and the defined boundary layer is phosphorous atoms of POPC. The calculated membrane thickness is 37.24 ± 0.49 Å, which is slightly thicker than that of pure POPC bilayer (37.00 ± 0.44 Å).…”

Section: Area Per Lipid and Membrane Thicknessmentioning

confidence: 99%

Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study

Wang

Meng²

2016

Molecular Simulation

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a tianjin Key laboratory of Molecular Design and Drug Discovery, tianjin institute of Pharmaceutical research, tianjin, P.r. china; b State Key laboratory of Drug Delivery technology and Pharmacokinetics, tianjin institute of Pharmaceutical research, tianjin, P.r. china ABSTRACT All-atom molecular dynamics simulations have been performed on cimetidine in the presence of a palmitoyloleoylphosphatidylcholine (POPC) bilayer. The free energy profile of a single cimetidine molecule passing across POPC bilayer displays a minimum at the interface of bilayer and water. Ten cimetidine molecules were inserted into POPC bilayer to obtain an 8 mol % drug model, and molecular dynamics results showed that cimetidine molecules reside at the polar region of POPC bilayer with sulphur atoms directing to the hydrophobic region. By comparing the one drug model with 8 mol % drug model, one can see that the central barrier to cross the membrane increases while the free energy in bulk water decreases, indicating that the ability of cimetidine passing across the POPC bilayer weakens at increased concentration. In addition, the free energy minimum shifts closer to the hydrophobic core. Our results indicate that with the increased drug concentration, it is more difficult for cimetidine to enter and pass across POPC bilayer.

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Molecular dynamics simulations of local anesthetic articaine in a lipid bilayer

Cited by 74 publications

References 55 publications

Endothelial Barrier Protection by Local Anesthetics

Endothelial Barrier Protection by Local Anesthetics

Effect of head group orientation on phospholipid assembly

Concentration effect of cimetidine with POPC bilayer: a molecular dynamics simulation study

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