Medicinal plant constituents interact with membrane-acting local anesthetics

Abstract

Specific constituents in medicinal plants have been suggested to act on lipid bilayers and modify the physicochemical properties of biomembranes as well as amphiphilic membrane-active drugs. The interactions between selected phytochemicals and local anesthetics were studied at a membrane lipid level to verify the possibility that their concomitant use may influence local anesthesia. Biomimetic lipid bilayer membranes were prepared as unilamellar vesicle suspensions by the injection method using different phospholipids and cholesterol to mimic the lipid composition of neuronal membranes. They were treated at 37 °C for 30 min with apple flavonoid phloretin, chili pepper capsaicinoid capsaicin, harmala alkaloid tetrahydroharman and local anesthetic lidocaine separately or in combination, followed by measuring fluorescence polarization to determine their induced membrane fluidity changes. Lidocaine increased the fluidity of biomimetic membranes at clinically-relevant concentrations. In contrast, phloretin (10 – 50 µM) and tetrahydroharman (10 – 500 nM) decreased the membrane fluidity, but capsaicin (50 – 100 µM) increased. Phloretin (25 µM) and tetrahydroharman (˜15 nM) inhibited or counteracted the membrane-fluidizing effects of lidocaine (0.05 – 1 mg/mL), whereas capsaicin (50 µM) potentiated. Such membrane interactions were also found in bupivacaine. Local anesthetics mechanistically act on neuronal membranes besides voltage-gated sodium channels. The antagonistic or synergistic membrane interactions with medicinal plant constituents suggest the potentially beneficial or adverse effects that the counteraction by phloretin would successfully discontinue anesthesia after the treatment and the cooperation with capsaicin should prolong the duration of nerve block, while the inhibition by tetrahydroharman might reduce the anesthetic efficacy in certain patients. The membrane interactivity will be also an experimental clue to discover the drug leads for anesthetic adjuncts.