Cytotoxicity of local anesthetics in human neuronal cells.
Abstract | BACKGROUND: In addition to inhibiting the excitation conduction process in peripheral nerves, local anesthetics (LAs) cause toxic effects on the central nervous system, cardiovascular system, neuromuscular junction, and cell metabolism. Different postoperative neurological complications are ascribed to the cytotoxicity of LAs, but the underlying mechanisms remain unclear. Because the clinical concentrations of LAs far exceed their EC(50) for inhibiting ion channel activity, ion channel block alone might not be sufficient to explain LA-induced cell death. However, it may contribute to cell death in combination with other actions. In this study, we compared the cytotoxicity of six frequently used LAs and will discuss the possible mechanism(s) underlying their toxicity. METHODS: In human SH-SY5Y neuroblastoma cells, viability upon exposure to six LAs ( bupivacaine, ropivacaine, mepivacaine, lidocaine, procaine, and chloroprocaine) was quantitatively determined by the MTT-(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra-odium bromide) colorimetry assay and qualitatively confirmed by fluorescence imaging, using the LIVE/DEAD assay reagents ( calcein/AM and ethidium homodimer-1). In addition, apoptotic activity was assessed by measuring the activation of caspase-3/-7 by imaging using a fluorescent caspase inhibitor (FLICA). Furthermore, LA effects on depolarization- and carbachol-stimulated intracellular Ca(2+)-responses were also evaluated. RESULTS: CONCLUSION: LAs can cause rapid cell death, which is primarily due to necrosis. Lidocaine and bupivacaine can trigger apoptosis with either increased time of exposure or increased concentration. These effects might be related to postoperative neurologic injury. Lidocaine, linked to the highest incidence of transient neurological symptoms, was not the most toxic LA, whereas bupivacaine, a drug causing a very low incidence of transient neurological symptoms, was the most toxic LA in our cell model. This suggests that cytotoxicity-induced nerve injury might have different mechanisms for different LAs and different target(s) other than neurons.
|
Authors | Rosalia Perez-Castro, Sohin Patel, Zayra V Garavito-Aguilar, Andrew Rosenberg, Esperanza Recio-Pinto, Jin Zhang, Thomas J J Blanck, Fang Xu |
Journal | Anesthesia and analgesia
(Anesth Analg)
Vol. 108
Issue 3
Pg. 997-1007
(Mar 2009)
ISSN: 1526-7598 [Electronic] United States |
PMID | 19224816
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Anesthetics, Local
- Muscarinic Agonists
- Potassium Channel Blockers
- Tetrazolium Salts
- Thiazoles
- Tetrodotoxin
- Tetraethylammonium
- Carbachol
- Caspases
- thiazolyl blue
- Calcium
|
Topics |
- Anesthetics, Local
(pharmacology)
- Apoptosis
(drug effects)
- Calcium
(metabolism)
- Carbachol
(pharmacology)
- Caspases
(metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Colorimetry
- Enzyme Activation
(drug effects)
- Humans
- Image Processing, Computer-Assisted
- Microscopy, Fluorescence
- Muscarinic Agonists
(pharmacology)
- Neurons
(drug effects, ultrastructure)
- Potassium Channel Blockers
(pharmacology)
- Tetraethylammonium
(pharmacology)
- Tetrazolium Salts
- Tetrodotoxin
(pharmacology)
- Thiazoles
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|