Cytotoxicity of Local Anesthetics in Human Neuronal Cells

Perez-Castro, Rosalia; Patel, Sohin; Garavito‐Aguilar, Zayra V.; Rosenberg, Andrew D.; Recio-Pinto, Esperanza; Zhang, Jin; Blanck, Thomas J. J.; Xu, Fang

doi:10.1213/ane.0b013e31819385e1

Cited by 215 publications

(183 citation statements)

References 42 publications

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“…Compounds shutting down intracellular reactions 403 concentrations of these drugs might contribute to clinical toxicity or side-effects, as reported previously (Perez-Castro et al, 2009;Motohashi, 2006;Vianna et al, 2001). The yeast system may contribute to elucidating the mechanisms of action and toxicity of the paralysing agents at the cellular level, and to the design of novel drugs, because the system can provide a genetic approach as well as easy and detailed evaluation.…”

Section: Compounds Shutting Down Intracellular Reactionssupporting

confidence: 57%

“…The clinical drugs are also known to have cytotoxic or neurotoxic effects (Kitagawa et al, 2004;Perez-Castro et al, 2009;Motohashi et al, 2006). At high concentrations, erythrocyte membrane and model membranes can be disrupted, and thus the toxic effects of drugs are considered to result from membrane lysis due to surfactant activities (Seeman, 1972;Kitagawa et al, 2004).…”

Section: Y Uesono Et Almentioning

confidence: 99%

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Structural analysis of compounds with actions similar to local anesthetics and antipsychotic phenothiazines in yeast

Uesono¹,

Toh‐e²,

Kikuchi³

et al. 2011

Yeast

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Local anesthetics and antipsychotic phenothiazines cause a rapid shutdown of both actin polarization and translation initiation in yeast cells, like some environmental stresses. These compounds all have an amphiphilic structure, surfactant activity and the ability to lyse yeast cells. To elucidate the structures responsible for the shutdown activity and cell lysis, we investigated a variety of amphiphiles. In the hydrophobic region, the straight alkyl structure was sufficient for the shutdown of actin polarization and translational initiation. In the hydrophilic region of the straight alkyl compounds, cationic trimethyl ammonium (TMA) and non-ionic hydroxyl structure (alcohols) shut down both reactions, while an anionic structure, sulphate, with a long alkyl chain (≥C6) shut down actin polarization only. On the compounds that shut down both reactions, including the clinical drugs, TMA compounds and alcohols, the potencies of shutdown and lysis exponentially increased with increasing the number of carbons in the hydrophobic region, whereas safety was affected by the structures of both hydrophilic and hydrophobic regions. These results indicate that the yeast system can easily evaluate clinical drugs, and provide a structural basis for designing compounds to shut down intracellular reactions.

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Section: Compounds Shutting Down Intracellular Reactionssupporting

confidence: 57%

Section: Y Uesono Et Almentioning

confidence: 99%

Structural analysis of compounds with actions similar to local anesthetics and antipsychotic phenothiazines in yeast

Uesono¹,

Toh‐e²,

Kikuchi³

et al. 2011

Yeast

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“…Both amides, lidocaine and bupivacaine, are uncouplers of oxidative phosphorylation 34 that collapse the pH gradient and electrical potential across the inner mitochondrial membrane. 35 Consequently, lidocaine induces cell apoptosis or necrosis by recruiting the intrinsic mitochondrial pathway in neuronal or nonneuronal systems, [35][36][37] but at concentrations higher than those used in this study (usually above 5 mM). However, this form of toxicity may be prominent for lower concentrations of the more lipophilic agent, bupivacaine.…”

Section: Discussionmentioning

confidence: 94%

Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes

Bawolak

Morissette

Marceau

2010

Can J Anesth/J Can Anesth

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Purpose Local anesthetics in their therapeutic concentration range cause a vacuolar cytopathology that has been observed in vivo and in various types of mammalian cells. We examined whether active concentration ranges of drugs and the kinetics of the vacuolar response are clinically relevant and whether this phenomenon is associated with cytotoxicity, autophagy, and cell stress signalling. Methods We compared procaine and lidocaine for morphological, functional, and signalling responses in a previously exploited non-neuronal system, primary smooth muscle cells. Several markers conjugated to fluorescent proteins allowed morphological and functional analysis of vacuolar cells. Signalling related to autophagy and cell stress was addressed (immunoblotting of cell lysates). Results Within 2-4 hr, lidocaine and procaine (C1 mM) induced massive cell vacuolization, a response abated by the V-ATPase inhibitor, bafilomycin A1, and activated macroautophagic signalling (LC3 II formation) but not other stress signalling (p38, ERK1/2, p53, no influence on serum-controlled Akt phosphorylation). Novel aspects of the morphological analysis include reduced LC3 labelling of the large vacuoles in cells treated with 3-methyl-adenine, inhibition of CD63 labelling of these vacuoles by co-expression of dominant negative Rab7, retention of secretory green fluorescent protein (GFP) possessing a signal sequence in vacuolar cells, and partial vacuole labelling with lysosomal-associated membrane protein 1 (LAMP1). Lidocaine (2.5-5 mM) was not overtly cytotoxic but arrested cell division over 48 hr. Conclusions V-ATPase-mediated sequestration of clinically relevant concentrations of local anesthetics sequentially involves vacuolization, macroautophagic signalling, and lysosome fusion to large vacuoles. Disruption of the secretory pathway and mitotic arrest were also observed over several hours without major cytotoxicity. RésuméObjectif A`concentration the´rapeutique, les anesthe´siques locaux causent une cytopathologie vacuolaire qui a e´teó bserve´e in vivo et dans divers types de cellules en culture. Nous avons examine´si les concentrations actives de me´dicaments et la cine´tique de cette re´ponse sont cliniquement pertinentes et si ce phe´nome`ne est associe´al a cytotoxicite´, l'autophagie et la signalisation de stress cellulaire.Méthode On a compare´les re´ponses morphologiques, fonctionnelles et signale´tiques a`la procaı¨ne et la lidocaı¨ne dans un syste`me non neuronal pre´alablement exploite´, le muscle lisse en culture primaire, afin d'e´clairer leurs effets toxicologiques a`des niveaux the´rapeutiques. Plusieurs marqueurs conjugue´s à des prote´ines fluorescentes ont permis des analyses morphologiques et fonctionnelles des cellules vacuolaires. La signalisation autophagique et celle relie´e au stress cellulaire ont e´te´e´value´es (immunobuvardage de lysats cellulaires). Résultats La lidocaı¨ne et la procaı¨ne (C1 mM) induisent en 2-4 hr une vacuolisation cellulaire massive, une

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“…Furthermore local anaesthetics may cause neural membrane lysis due to detergent properties (Kitagawa et al 2004). The size of these effects is strongly influenced by a prolonged duration of exposure and higher concentration of the local anaesthetics, with in vitro the lowest neurotoxicty for procaine, mepivacaine and lidocaïne compared with ropivacaine and bupivacaine (Hogan 2008;Perez-Castro et al 2009), however most clinical relevant toxicity is attributed to high concentrations of lidocaïne (Zink & Graf 2003).…”

Section: Neurotoxicitymentioning

confidence: 99%