title: In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity.
abstract: BACKGROUND
  Animal models show us that specific activation of the p38 mitogen-activated protein kinase (MAPK) may be a pivotal step in lidocaine neurotoxicity, but this has not been investigated in the case of two very widely used local anesthetics, bupivacaine and ropivacaine. We investigated the hypotheses that these drugs (A) are less neurotoxic than the prototype local anesthetic, lidocaine (B) are selectively toxic for subcategories of dorsal root ganglion neurons and (C) induce activation of either p38 MAPK or related enzymes, such as the c-jun terminal N-kinase (JNK) and extracellular signal-regulated kinase (ERK).
  
  
  METHODS
  We incubated primary sensory neuron cultures with doses of lidocaine, bupivacaine, and ropivacaine equipotent at blocking sodium currents. Next, we sought to determine potential selectivity of bupivacaine and ropivacaine toxicity on neuron categories defined by immunohistochemical staining, or size. Subsequently, the involvement of p38 MAPK, JNK, and ERK was tested using enzyme-linked immunosorbent assays. Finally, the relevance of MAPK pathways in bupivacaine- and ropivacaine-induced neurotoxicity was determined by selectively inhibiting activity of p38 MAPK, JNK, and ERK.
  
  
  RESULTS
  We found that the neurotoxic potency of bupivacaine and ropivacaine is dose-dependent and similar in vitro, but is not selective for any of the investigated subgroups of neurons. Neurotoxicity of bupivacaine and ropivacaine was mediated, at least in part, by MAPKs. Specifically, we demonstrated the relevance of both p38 MAPK and JNK pathways for the neurotoxicity of bupivacaine and characterized the involvement of the p38 MAPK pathway in the neurotoxicity of ropivacaine.
  
  
  CONCLUSIONS
  Given equipotent doses, the neurotoxic potential of lidocaine does not appear to be significantly different from that of bupivacaine and ropivacaine in vitro. Moreover, bupivacaine and ropivacaine do not exert their neurotoxicity differently on specific subsets of dorsal root ganglion neurons. Their neurotoxic effects are brought about through the activation of specific MAPKs; the specific pharmacologic inhibition of these kinases attenuates toxicity in vitro.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstr. 35, 6020 Innsbruck, Austria. philipp.lirk@i-med.ac.at
authors.forename: Philipp
authors.initials: P
authors.lastname: Lirk
authors.forename: Ingrid
authors.initials: I
authors.lastname: Haller
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Colvin
authors.forename: Leopold
authors.initials: L
authors.lastname: Lang
authors.forename: Bettina
authors.initials: B
authors.lastname: Tomaselli
authors.forename: Lars
authors.initials: L
authors.lastname: Klimaschewski
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
mesh_terms: D000577:Amides / Q000633:toxicity*; D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002045:Bupivacaine / Q000633:toxicity*; D002070:Butadienes / Q000494:pharmacology; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000201:enzymology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008012:Lidocaine / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects* / Q000201:enzymology; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077212:Ropivacaine; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D000779:Anesthetics, Local; D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D015222:Sodium Channels; C113580:U 0126; C432165:pyrazolanthrone; D000077212:Ropivacaine; D008012:Lidocaine; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002045:Bupivacaine