NSAIDs Alter Lipid Bilayer Mechanical Properties

Abstract

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a class of widely prescribed medications that have analgesic, antipyretic, anti-thrombotic and anti-inflammatory properties. Their primary mechanism of action is through non-selective inhibition of the Cyclo-oxygenase enzymes (COX-1 and COX-2), which mediates many of the clinical - and side - effects of NSAIDs. Other effects are mediated through COX-independent mechanisms, however. Given that NSAIDs are amphiphiles, that they modulate the function of many different, structurally unrelated membrane proteins, and that the lipid bilayer serves as a gate-keeper/regulator for many different cell functions, we tested whether NSAIDs could alter lipid bilayer material properties. To measure such changes in bilayer material properties, we used gramicidin A (gA) channels as molecular force transducers. We found that salicylate, ibuprofen, diclofenac, sulindac sulfide and flurbiprofen are potent modifiers of bilayer properties. At pH 7, NSAIDs were found to increase both the lifetime and appearance rate of channels formed by both short (13-residue) and long 15-residue gramicidin analogues, with the larger effects on the shorter channels - the channels with the larger hydrophobic mismatch, which shows that NSAIDs decrease lipid bilayer stiffness by increasing the bilayer elasticity. These effects were achieved at the high end of clinically relevant concentrations. This suggests that in both the clinical and research setting, NSAIDs may have effects that arise from modulation of lipid bilayer mechanical properties.