PMID- 36191347
OWN - NLM
STAT- MEDLINE
DCOM- 20230306
LR  - 20230306
IS  - 1472-8206 (Electronic)
IS  - 0767-3981 (Linking)
VI  - 37
IP  - 2
DP  - 2023 Apr
TI  - Bupivacaine inhibits the TLR4- and TLR2-Myd88/NF-kappaB pathways in human leukocytes.
PG  - 347-358
LID - 10.1111/fcp.12836 [doi]
AB  - 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 Toll like 
      receptor 4 (TLR4)- and TLR2-myeloid differentiation primary response 88 
      (MyD88)-nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) 
      pathways. We measured tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 
      (PGE2) release, p38 mitogen-activated protein kinase (MAP-kinase) phosphorylation 
      and translocation of NF-kappaB in human peripheral blood mononuclear cells (hPBMCs) 
      and human monocytes challenged with lipopolysaccharide (LPS) or tripalmitoylated 
      lipopeptide Pam3CysSerLys4 (Pam3CSK4) 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-myeloid 
      differentiation protein 2 (MD-2) complex and to the TLR2/TLR1 heterodimer were 
      performed. In PBMCs, bupivacaine from 0.1 to 100 muM inhibited LPS-induced TNF-alpha 
      and PGE2 secretion, phosphorylation of p38 and nuclear translocation of NF-kappaB in 
      monocytes. Bupivacaine similarly inhibited the effects of Pam3CSK4 on TNF-alpha 
      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. Contrary to numerous experiments 
      performed with supratherapeutic doses, our results were obtained with 
      concentrations of bupivacaine as low as 0.1 muM. 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-kappaB pathways.
CI  - (c) 2022 Societe Francaise de Pharmacologie et de Therapeutique. Published by John 
      Wiley & Sons Ltd.
FAU - Binczak, Marie
AU  - Binczak M
AD  - Departement d'Anesthesie, Institut Gustave-Roussy, Villejuif, France.
FAU - Purenne, Emilien
AU  - Purenne E
AD  - Hopital Prive des Peupliers, Paris, France.
FAU - Beloeil, Helene
AU  - Beloeil H
AD  - UMR 991, Universite Rennes 1, Rennes, France.
FAU - Benhamou, Dan
AU  - Benhamou D
AD  - Laboratoire d'anesthesie, Paris-Saclay University and INSERM U1195 Faculte de 
      Medecine de Bicetre, Le Kremlin-Bicetre, France.
FAU - Mazoit, Jean Xavier
AU  - Mazoit JX
AUID- ORCID: 0000-0003-3641-7046
AD  - Laboratoire d'anesthesie, Paris-Saclay University and INSERM U1195 Faculte de 
      Medecine de Bicetre, Le Kremlin-Bicetre, France.
LA  - eng
GR  - MAPAR/
GR  - Institut national de la sante et de la recherche medicale/
GR  - Mises au Point en Anesthesie-Reanimation/
PT  - Journal Article
DEP - 20221011
PL  - England
TA  - Fundam Clin Pharmacol
JT  - Fundamental & clinical pharmacology
JID - 8710411
RN  - 0 (NF-kappa B)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - Y8335394RO (Bupivacaine)
RN  - 0 (TLR2 protein, human)
RN  - 0 (TLR4 protein, human)
SB  - IM
MH  - Humans
MH  - *NF-kappa B/metabolism
MH  - *Toll-Like Receptor 4/metabolism
MH  - Toll-Like Receptor 2/genetics/metabolism
MH  - Myeloid Differentiation Factor 88/genetics/metabolism/pharmacology
MH  - Signal Transduction
MH  - Leukocytes, Mononuclear/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Dinoprostone
MH  - Molecular Docking Simulation
MH  - Bupivacaine/pharmacology
MH  - HEK293 Cells
OTO - NOTNLM
OT  - Toll-like receptors
OT  - bupivacaine
OT  - inflammation
OT  - local anesthetics
EDAT- 2022/10/04 06:00
MHDA- 2023/03/07 06:00
CRDT- 2022/10/03 17:52
PHST- 2022/08/31 00:00 [revised]
PHST- 2022/06/05 00:00 [received]
PHST- 2022/10/02 00:00 [accepted]
PHST- 2022/10/04 06:00 [pubmed]
PHST- 2023/03/07 06:00 [medline]
PHST- 2022/10/03 17:52 [entrez]
AID - 10.1111/fcp.12836 [doi]
PST - ppublish
SO  - Fundam Clin Pharmacol. 2023 Apr;37(2):347-358. doi: 10.1111/fcp.12836. Epub 2022 
      Oct 11.