In Vitro, Inhibition of Mitogen-Activated Protein Kinase Pathways Protects Against Bupivacaine- and Ropivacaine-Induced Neurotoxicity

• DOI: 10.1213/ane.0b013e318168514b
• Publication Date: 2008-04-16T07:04:05Z
• Authors: Philipp Lirk; Ingrid Haller; Hans Peter; Leopold Lang; Bettina Tomaselli; Lars Klimaschewski; Peter Gerner
• Keywords: Anthracenes; Dose-Response Relationship, Drug; Cell Survival; Imidazoles; JNK Mitogen-Activated Protein Kinases; Lidocaine; Amides; Bupivacaine; Membrane Potentials; 3. Good health; Enzyme Activation; 03 medical and health sciences; 0302 clinical medicine; Cytoprotection; Ganglia, Spinal; Butadienes; Animals; Female; Anesthetics, Local; Mitogen-Activated Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Cells, Cultured; Cell Size

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).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.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.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.