Neurotoxicity of lidocaine involves specific activation of the p38 mitogen-activated protein kinase, but not extracellular signal-regulated or c-jun N-terminal kinases, and is mediated by arachidonic acid metabolites.
BACKGROUND
Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways.


METHODS
The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity.


RESULTS
All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures.


CONCLUSIONS
Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.
Haller
Ingrid
I
Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria.
Hausott
Barbara
B
Tomaselli
Bettina
B
Keller
Christian
C
Klimaschewski
Lars
L
Gerner
Peter
P
Lirk
Philipp
P
D000779:Anesthetics, Local / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008012:Lidocaine / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009637:Masoprocol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D016716:PC12 Cells; D010641:Phenotype; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000779:Anesthetics, Local; D016859:Lipoxygenase Inhibitors; D009498:Neurotoxins; D016718:Arachidonic Acid; D009637:Masoprocol; D008012:Lidocaine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases