Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1

Abstract

BackgroundIsoflurane in clinical use is a racemate of S- and R-isoflurane. Previous studies have demonstrated that the effects of S-isoflurane on relevant anesthetic targets might be modestly stronger (less than 2-fold) than R-isoflurane. The X-ray crystallographic structure of the immunological target, leukocyte function-associated antigen-1 (LFA-1) with racemic isoflurane suggested that only S-isoflurane bound specifically to this protein. If so, the use of specific isoflurane enantiomers may have advantage in the surgical settings where a wide range of inflammatory responses is expected to occur. Here, we have further tested the hypothesis that isoflurane enantioselectivity is apparent in solution binding and functional studies.MethodsFirst, binding of isoflurane enantiomers to LFA-1 was studied using 1-aminoanthracene (1-AMA) displacement assays. The binding site of each enantiomer on LFA-1 was studied using the docking program GLIDE. Functional studies employed the flow-cytometry based ICAM binding assay.ResultsBoth enantiomers decreased 1-AMA fluorescence signal (at 520 nm), indicating that both competed with 1-AMA and bound to the αL I domain. The docking simulation demonstrated that both enantiomers bound to the LFA-1 “lovastatin site.” ICAM binding assays showed that S-isoflurane inhibited more potently than R-isoflurane, consistent with the result of 1-AMA competition assay.ConclusionsIn contrast with the x-ray crystallography, both enantiomers bound to and inhibited LFA-1. S-isoflurane showed slight preference over R-isoflurane.

Effects of propofol and surgery on neuropathology and cognition in the 3xTgAD Alzheimer transgenic mouse model

“…Ultimately, the precise mechanism might be difficult to determine because propofol, like many general anaesthetics, is a promiscuous drug, having hundreds of molecular targets. 39 Potential targets mediating a protective effect could include several mitochondrial proteins, leucocyte integrins, 40 and sirtuin deacetylases. 41 The mortality associated with the present study is higher than observed in the clinical application of propofol for surgery.…”

Surgical Site Infections and Perioperative Optimization of Host Immunity by Selection of Anesthetics

“…A number of direct anesthetic targets on immune cells have been reported. These targets include adhesion molecules integrins [79][80][81][82][83][84], TLRs [85][86][87], and intracellular molecule Rap1 [76]. Volatile anesthetic integrin targets include leukocyte-function associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), both of which are expressed on neutrophils.…”

Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

“…This approach has verified a large number of plausible targets, including, but not limited to: specific ligand-gated ion channels [147,148], voltage-gated channels [149,150], hyperpolarizationactivated cyclic nucleotide (HCN)-gated and tandem pore potassium (K 2 P) channels [151], and mitochondrial proteins [152]. Attempts to distinguish functional significance of these many targets has used sensitivity, stereoselectivity [153], alkanol cutoff effect [9,154], and other phenomenological observations, some of which has caused further ambiguity. Nevertheless, this has been a powerful approach that has constrained the degree of potential complexity.…”