Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro  and In Vivo

Lirk, Philipp; Haller, Ingrid; Myers, Robert R.; Klimaschewski, Lars; Kau, Yi-Chuan; Hung, Ying; Gerner, Peter

doi:10.1097/00000542-200606000-00023

Cited by 62 publications

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“…SH‐SY5Y cells were treated with bupivacaine, lidocaine, tetracaine, procaine and ropivacaine at different dosages according to the previous studies 7, 18, 19, 21, 22, 23, 24. Cell viability was evaluated by MTT assay 24 hrs after LAs challenge.…”

Section: Resultsmentioning

confidence: 99%

“…To address these questions, we treated human neuroblastoma SH‐SY5Y cells with both lipid LAs (procaine and tetracaine) and amide LAs (bupivacaine, lidocaine and ropivacaine) at previously described dosages 18, 19, 21, 22, 23, 24. The results showed that all the examined LAs up‐regulated autophagic process and inhibited tuberin/mTOR/p70S6K signalling in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Xiong

Kong

Dai

et al. 2016

J Cellular Molecular Medi

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The local anaesthetics (LAs) are widely used for peripheral nerve blocks, epidural anaesthesia, spinal anaesthesia and pain management. However, exposure to LAs for long duration or at high dosage can provoke potential neuronal damages. Autophagy is an intracellular bulk degradation process for proteins and organelles. However, both the effects of LAs on autophagy in neuronal cells and the effects of autophagy on LAs neurotoxicity are not clear. To answer these questions, both lipid LAs (procaine and tetracaine) and amide LAs (bupivacaine, lidocaine and ropivacaine) were administrated to human neuroblastoma SH‐SY5Y cells. Neurotoxicity was evaluated by MTT assay, morphological alterations and median death dosage. Autophagic flux was estimated by autolysosome formation (dual fluorescence LC3 assay), LC3‐II generation and p62 protein degradation (immunoblotting). Signalling alterations were examined by immunoblotting analysis. Inhibition of autophagy was achieved by transfection with beclin‐1 siRNA. We observed that LAs decreased cell viability in a dose‐dependent manner. The neurotoxicity of LAs was tetracaine > bupivacaine > ropivacaine > procaine > lidocaine. LAs increased autophagic flux, as reflected by increases in autolysosome formation and LC3‐II generation, and decrease in p62 levels. Moreover, LAs inhibited tuberin/mTOR/p70S6K signalling, a negative regulator of autophagy activation. Most importantly, autophagy inhibition by beclin‐1 knockdown exacerbated the LAs‐provoked cell damage. Our data suggest that autophagic flux was up‐regulated by LAs through inhibition of tuberin/mTOR/p70S6K signalling, and autophagy activation served as a protective mechanism against LAs neurotoxicity. Therefore, autophagy manipulation could be an alternative therapeutic intervention to prevent LAs‐induced neuronal damage.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Xiong

Kong

Dai

et al. 2016

J Cellular Molecular Medi

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“…The more severe sequelae after spinal anesthesia, the cauda equina syndrome and lumbosacral neuropathies (49), might be caused by neurotoxic effects of LAs. Several molecular mechanisms have been considered to mediate LA-induced cytotoxicity, including a direct membrane disruption (6), mitochondrial dysfunction (7), and activation of the p38 mitogen-activated protein kinase involved in apoptosis (8,9). It is conceivable that Ca 2+ influx as a result of LA-mediated TRPV1 activation contributes to cell death by inducing necrotic and apoptotic mechanisms (16,50).…”

Section: Figurementioning

confidence: 99%

“…Neurotoxicity is a well-known side effect of highly concentrated LAs applied in the vicinity of neuronal structures (5). Several molecular mechanisms have been considered to mediate LA-induced cytotoxicity leading to cell death, including direct membrane disruption (6), mitochondrial dysfunction (7), and activation of the p38 mitogen-activated protein kinase involved in apoptosis (8,9). Furthermore, LAs were previously demonstrated to directly depolarize sensory neurons by mediating an increase in intracellular Ca 2+ ([Ca 2+ ] i ) (10,11).…”

Section: Introductionmentioning

confidence: 99%

The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

Leffler

Fischer²,

Rehner³

et al. 2008

J. Clin. Invest.

113

180

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Local anesthetics (LAs) block the generation and propagation of action potentials by interacting with specific sites of voltage-gated Na + channels. LAs can also excite sensory neurons and be neurotoxic through mechanisms that are as yet undefined. Nonspecific cation channels of the transient receptor potential (TRP) channel family that are predominantly expressed by nociceptive sensory neurons render these neurons sensitive to a variety of insults. Here we demonstrated that the LA lidocaine activated TRP channel family receptors TRPV1 and, to a lesser extent, TRPA1 in rodent dorsal root ganglion sensory neurons as well as in HEK293t cells expressing TRPV1 or TRPA1. Lidocaine also induced a TRPV1-dependent release of calcitonin gene-related peptide (CGRP) from isolated skin and peripheral nerve. Lidocaine sensitivity of TRPV1 required segments of the putative vanilloid-binding domain within and adjacent to transmembrane domain 3, was diminished under phosphatidylinositol 4,5-bisphosphate depletion, and was abrogated by a point mutation at residue R701 in the proximal C-terminal TRP domain. These data identify TRPV1 and TRPA1 as putative key elements of LA-induced nociceptor excitation. This effect is sufficient to release CGRP, a key component of neurogenic inflammation, and warrants investigation into the role of TRPV1 and TRPA1 in LA-induced neurotoxicity.

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“…In addition, anti-proliferative effects of LAs on human cancer cells have been reported [10,11] . Several studies suggest that the LA-induced neurotoxicity may involve mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways [12][13][14][15] . Compared to neurotoxicity, the molecular mechanisms by which the LAs induce myotoxicity remain poorly understood, although myotoxicity could have severe consequences in clinically relevant settings [16,17] .…”

Section: Introductionmentioning

confidence: 99%

Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways

Maurice

Gan

et al. 2010

Acta Pharmacol Sin

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Aim:The adverse effects of local anesthetics (LAs) on wound healing at surgical sites have been suggested, and may be related to their cytotoxicity. This study was aimed to compare the cellular toxicity of bupivacaine and lidocaine (two well-known LAs), and to explore the molecular mechanism(s). Methods: Toxicity of bupivacaine and lidocaine was assessed in cultured mouse C2C12 myoblasts by cell viability and apoptosis assays. effects of LAs on extracellular signal-regulated kinase (erK) and protein kinase b (Akt) activation, which are essential for cell proliferation and survival, were evaluated by immunoblotting. Results: both LAs, especially bupivacaine, prevented cell growth and caused cell death in a dose-dependent manner. The half maximal inhibitory concentrations (IC 50 ) for bupivacaine and lidocaine were 0.49±0.04 and 3.37±0.53 mmol/L, respectively. When applied at the same dilutions of commercially available preparations, the apoptotic effect induced by bupivacaine was more severe than that of lidocaine in C2C12 cells. Furthermore, bupivacaine significantly diminished the ERK activation, which may underlie its anti-proliferative actions. both LAs suppressed Akt activation, which correlated with their effects on apoptosis. Conclusion: Our study demonstrated that, when used at the same dilutions from clinically relevant concentrations, bupivacaine is more cytotoxic than lidocaine in vitro. Anti-proliferation and cell death with concomitant apoptosis mediated by bupivacaine may offer an explanation for its adverse effects in vivo (eg slowing wound healing at the surgical sites). A less toxic, long-acting anesthetic may be needed.

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Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro and In Vivo

Cited by 62 publications

References 0 publications

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons

Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways

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