Abstract
Background
Local anesthetics have anti-inflammatory effects. Because most previous experiments were performed with supra-therapeutic concentrations, we measured the effects of clinically relevant concentrations of bupivacaine on the TLR4- and TLR2-MyD88-NF-κB pathways.
Methods
We measured TNF-α and PGE2 release, p38 MAP-kinase phosphorylation and translocation of NF-κB in human peripheral blood mononuclear cells (hPBMC) and human monocytes challenged with LPS (lipopolysaccharide) or Pam3CSK4 (tripalmitoylated lipopeptide Pam3CysSerLys4) in the presence or absence of bupivacaine. Similarly, we measured the effect of bupivacaine on HEK293 cells expressing the hTLR4 and the hTLR2 genes and challenged with LPS or Pam3CSK4. Finally, molecular docking simulations of R(+)- and S(-)-bupivacaine binding to the TLR4-MD-2 complex and to the TLR2/TLR1 heterodimer were performed.
Results
In PBMCs, bupivacaine from 0.1 to 100 μM inhibited LPS-induced TNF-α and PGE2 secretion, phosphorylation of p38 and nuclear translocation of NF-κB in monocytes. Bupivacaine similarly inhibited the effects of Pam3CSK4 on TNF-α secretion. Bupivacaine inhibited the effect of LPS on HEK293 cells expressing the human TLR4 receptor and the effect of Pam3CSK4 on HEK293 cells expressing the human TLR2 receptor. Molecular docking showed that bupivacaine binds to the MD-2 co-receptor of TLR4 and to the TLR2 receptor.
Conclusions
Contrary to numerous experiments performed with supratherapeutic doses, our results were obtained with concentrations of bupivacaine as low as 0.1 μM. We conclude that bupivacaine modulates the inflammatory reactions such as those observed after surgery or trauma, at least partly by inhibiting the TLR4- and TLR2-NF-κB pathways.
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