The primary mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) is inhibition
of prostaglandin production mediated by cyclooxygenase. Given the possible association
of cyclooxygenase-2, but not cyclooxygenase-1, with membrane lipid rafts, we assessed
whether the lipid raft membrane interactivity of NSAIDs correlates with cyclooxygenase-2
selectivity. Lipid raft model membranes and reference membranes were prepared with
1,2-dioleoylphosphatidylcholine/sphingomyelin/cholesterol and 1,2-dipalmitoylphosphatidylcholine,
respectively. After treating the membranes with 2–50 μM NSAIDs at pH 7.4, 6.5, and
5.5, fluorescence polarization was measured to determine their membrane interactivity.
Conventional NSAIDs (diclofenac, ibuprofen, indomethacin, aspirin, and flurbiprofen)
and Coxibs (lumiracoxib, etoricoxib, celecoxib, valdecoxib, and rofecoxib) decreased
membrane fluidity, whereas Oxicams (meloxicam, piroxicam, tenoxicam, and lornoxicam)
increased. Membrane effects of NSAIDs were so dependent on medium pH that they significantly
increased with reducing pH from 7.4 to 5.5. Under inflammatory acidic conditions,
the lipid raft membrane interactivity of NSAIDs was more likely to correlate with
cyclooxygenase-2 selectivity than the reference membrane interactivity. It is hypothesized
that NSAIDs may interact with lipid raft membranes to induce membrane fluidity changes
with the potency corresponding to cyclooxygenase-2 inhibition, disrupting the structural
and functional integrity of lipid rafts to affect the activity of cyclooxygenase-2
localized in lipid rafts, resulting in cyclooxygenase-2 selective inhibition.
