Mitochondrial injury and caspase activation by the local anesthetic lidocaine
| Autor: | Karl Heinz Spittler, Gregory J. Gores, Michael E. Johnson, Hongxun Wang, Cindy B. Uhl |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Necrosis
Lidocaine medicine.drug_class medicine.medical_treatment Neurotoxins Apoptosis Antiarrhythmic agent Buffers Membrane Potentials Oxygen Consumption medicine Animals Neurons Afferent Anesthetics Local Caspase Cells Cultured Fluorescent Dyes Microscopy Confocal biology Local anesthetic business.industry Neurotoxicity Cytochromes c medicine.disease Flow Cytometry Mitochondria Rats Enzyme Activation Anesthesiology and Pain Medicine Anticonvulsant Spinal Cord Cell culture Anesthesia Caspases biology.protein medicine.symptom business medicine.drug |
| Zdroj: | Anesthesiology. 101(5) |
| ISSN: | 0003-3022 |
| Popis: | Background Lidocaine, a local anesthetic, can be neurotoxic. However, the cellular mechanisms of its neurotoxicity at concentrations encountered during spinal anesthesia remain unclear. Methods The authors examined the mechanisms of lidocaine neurotoxicity in the ND7 cell line derived from rat dorsal root ganglion. Individual neurons were assayed by flow cytometry or microscopy using fluorescent probes of plasma membrane integrity, mitochondrial membrane potential, caspase activity, phospholipid membrane asymmetry, and mitochondrial cytochrome c release. Results In the ND7 cell line, lidocaine at 185 mm x 10 min to 2.3 mm x 24 h caused necrosis or late apoptosis. Equimolar Tris buffer and equipotent tetrodotoxin controls were not toxic, indicating that neither osmotic nor Na-blocking effects explain lidocaine neurotoxicity. The earliest manifestation of lidocaine neurotoxicity was complete loss of mitochondrial membrane potential within 5 min after exposure to lidocaine at a concentration of 19 mm or greater. Consistent with these data, 37 mm lidocaine (1%) induced release of mitochondrial cytochrome c into the cytoplasm, as well as plasma membrane blebbing, loss of phosphatidylserine membrane asymmetry, and caspase activation, with release of mitochondrial cytochrome c to the cytoplasm within 2 h. Treatment with z-VAD-fmk, a specific inhibitor of caspases, prevented caspase activation and delayed but did not prevent neuronal death, but did not inhibit the other indicators of apoptosis. Conclusions Collectively, these data indicate that lidocaine neurotoxicity involves mitochondrial dysfunction with activation of apoptotic pathways. |
| Databáze: | OpenAIRE |
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