Mizogami Maki, Iida Hiroki, Tsuchiya Hironori
Anesthesiology and Pain Relief Center, Central Japan International Medical Center, Minokamo 505-8510, Gifu, Japan.
Department of Dental Basic Education, Asahi University School of Dentistry, Mizuho 501-0296, Gifu, Japan.
Membranes (Basel). 2025 Sep 22;15(9):284. doi: 10.3390/membranes15090284.
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.
非甾体抗炎药（NSAIDs）的主要作用机制是抑制由环氧化酶介导的前列腺素生成。鉴于环氧化酶-2（而非环氧化酶-1）可能与膜脂筏相关联，我们评估了NSAIDs的脂筏膜相互作用是否与环氧化酶-2选择性相关。分别用1,2 - 二油酰磷脂酰胆碱/鞘磷脂/胆固醇和1,2 - 二棕榈酰磷脂酰胆碱制备脂筏模型膜和对照膜。在pH 7.4、6.5和5.5条件下用2 - 50 μM的NSAIDs处理膜后，测量荧光偏振以确定它们的膜相互作用。传统NSAIDs（双氯芬酸、布洛芬、吲哚美辛、阿司匹林和氟比洛芬）以及昔布类药物（鲁米昔布、依托考昔、塞来昔布、伐地考昔和罗非昔布）降低了膜流动性，而昔康类药物（美洛昔康、吡罗昔康、替诺昔康和氯诺昔康）则增加了膜流动性。NSAIDs的膜效应非常依赖于介质pH，随着pH从7.4降至5.5，它们的效应显著增加。在炎症酸性条件下，NSAIDs的脂筏膜相互作用比对照膜相互作用更可能与环氧化酶-2选择性相关。据推测，NSAIDs可能与脂筏膜相互作用，以对应于环氧化酶-2抑制效力的程度诱导膜流动性变化，破坏脂筏的结构和功能完整性，从而影响定位于脂筏中的环氧化酶-2的活性，导致环氧化酶-2选择性抑制。
