In Vitro, Inhibition of Mitogen-Activated Protein Kinase Pathways Protects Against Bupivacaine- and Ropivacaine-Induced Neurotoxicity
| Autor: | Leopold Lang, I. Haller, Lars Klimaschewski, Peter Gerner, Hans Peter Colvin, Philipp Lirk, Bettina Tomaselli |
|---|---|
| Přispěvatelé: | Other departments |
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Cell Survival Pyridines p38 mitogen-activated protein kinases Pharmacology p38 Mitogen-Activated Protein Kinases Sodium Channels Membrane Potentials Rats Sprague-Dawley Ganglia Spinal Nitriles Butadienes medicine Animals Ropivacaine Neurons Afferent Anesthetics Local Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein kinase A Protein Kinase Inhibitors Cells Cultured Cell Size Anthracenes Bupivacaine Dose-Response Relationship Drug biology business.industry Imidazoles JNK Mitogen-Activated Protein Kinases Neurotoxicity Lidocaine medicine.disease Amides Cytoprotection Rats Enzyme Activation Phenotype Anesthesiology and Pain Medicine Mitogen-activated protein kinase biology.protein Female Mitogen-Activated Protein Kinases business medicine.drug |
| Zdroj: | Anesthesia and analgesia, 106(5), 1456-64, table of contents. Lippincott Williams and Wilkins |
| ISSN: | 0003-2999 |
| DOI: | 10.1213/ane.0b013e318168514b |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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