Bupivacaine Myotoxicity Is Mediated by Mitochondria

Irwin, William; Fontaine, Éric; Agnolucci, Laura; Penzo, Daniele; Betto, Romeo; Bortolotto, Susan K.; Reggiani, Carlo; Salviati, G.; Bernardi, Paolo

doi:10.1074/jbc.m108938200

Cited by 163 publications

(124 citation statements)

References 57 publications

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“…In rat hippocampal slices, application of millimolar concentrations of lidocaine, but not bupivacaine, resulted in elevated expression of cleaved caspase 3, the primary executioner of apoptosis [38] . Active oxidative metabolism involving mitochondrial dysfunction and alterations of Ca 2+ homeostasis has been also suggested in bupivacaine-induced myotoxicity [36] . These findings raise an interesting possibility that some, if not all, of these pathways could modulate specific LA-induced myotoxicity independently or collaboratively.…”

Section: Wwwnaturecom/aps Maurice Jm Et Almentioning

confidence: 99%

“…Studies on both acute and longterm myotoxic effects of LAs after continuous peripheral nerve blocks in a clinically relevant setting reaffirmed bupivacaine's exceptional rate of myotoxicity [6,7] . Excessively increased intracellular [Ca 2+ ] level due to an alteration of Ca 2+ homeostasis has been suggested as a cause of bupivacaine-induced muscle cell death [35] , perhaps mediated by mitochondria [36] . However, detailed molecular mechanisms, especially the signaling pathways, by which the LAs exert their cytotoxicities remain to be explored.…”

Section: Wwwnaturecom/aps Maurice Jm Et Almentioning

confidence: 99%

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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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Section: Wwwnaturecom/aps Maurice Jm Et Almentioning

confidence: 99%

Section: Wwwnaturecom/aps Maurice Jm Et Almentioning

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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“…A small number of studies have attempted to establish the mechanisms by which LAs induce chondrotoxicity. It has been shown that LAs may cause mitochondrial dysfunction, inhibition of voltage-gated Na + and Ca 2+ channels, or potassium channel blockade [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro by inhibiting the p53-dependent mitochondrial apoptotic pathway

2016

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Aim: Intra-articular injection of local anesthetics (LAs) is a common procedure for therapeutic purposes. However, LAs have been found toxic to articular cartilage, and hyaluronan may attenuate this toxicity. In this study we investigated whether hyaluronan attenuated lidocaine-induced chondrotoxicity, and if so, to elucidate the underlying mechanisms. Methods: Human chondrocyte cell line SW1353 and newly isolated murine chondrocytes were incubated in culture medium containing hyaluronan and/or lidocaine for 72 h. Cell viability was evaluated using MTT assay. Cell apoptosis was detected with DAPI staining, caspase 3/7 activity assay and flow cytometry. Cell cycle distributions, ROS levels and mitochondrial membrane potential (ΔΨm) were determined using flow cytometry. The expression of p53 and p53-regulated gene products was measured with Western blotting. Results: Lidocaine (0.005%−0.03%) dose-dependently decreased the viability of SW1353 cells. This local anesthetic (0.015%, 0.025%) induced apoptosis, G 2 /M phase arrest and loss of ΔΨm, and markedly increased ROS production in SW1353 cells. Hyaluronan (50−800 µg/mL) alone did not affect the cell viability, but co-treatment with hyaluronan (200 µg/mL) significantly attenuated lidocaine-induced apoptosis and other abnormalities in SW1353 cells. Furthermore, co-treatment with lidocaine and hyaluronan significantly decreased the levels of p53 and its transcription targets Bax and p21 in SW1353 cells, although treatment with lidocaine alone did not significantly change these proteins. Similar results were obtained in ex vivo cultured murine chondrocytes. Conclusion: Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro through inhibiting the p53-dependent mitochondrial apoptotic pathway.

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“…Besides, mitochondrial dysfunction results in ATP depletion 47 and in turn is expected to have a major impact on intracellular Ca 2+ homeostasis 48 . In addition, active oxidative metabolism is a key determinant in bupivacaine toxicity, and bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death, and Ca 2+ dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role 49 . Longacting local anesthetics induce marked negative inotropic and lusitropic effects on cardiomyocytes and such effect was mainly because of the impairment of calcium handling 50 .…”

Section: Local Anesthetics and Mitochondrionmentioning

confidence: 99%

A cardiolipina é o alvo da cardiotoxicidade dos anestésicos locais?

Shen¹,

Xu²,

Qian³

et al. 2010

Rev. Bras. Anestesiol.

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Is Cardiolipin the Target of Local Anesthetic Cardiotoxicity?Background and objectives: Local anesthetics are used broadly to prevent or reverse acute pain and treat symptoms of chronic pain. Local anesthetic-induced cardiotoxic reaction has been considered the accidental event without currently effective therapeutic drugs except for recently reported intralipid infusion whose possible mechanism of action is not well known. Contents:Cardiolipin, an anionic phospholipid, plays a key role in determining mitochondrial respiratory reaction, fatty acid metabolism and cellular apoptosis. Mitochondrial energy metabolism dysfunction is suggested as associated with local anesthetic cardiotoxicity, from an in vitro study report that the local anesthetic cardiotoxicity may be due to the strong electrostatic interaction of local anesthetics and cardiolipin in the mitochondria membrane, although there is a lack for experimental evidence. Herein we hypothesized that local anesthetic-cardiolipin interactions were the major determinant of local anesthetic-associated cardiotoxic reaction, established by means of theoretic and structural biological methods. This interacting model would give an insight on the underlying mechanism of local anesthetic cardiotoxicity and provide clues for further in depth research on designing preventive drugs for such inadvertent accidence in routine clinical practice. Conclusions:The interaction between local anesthetic and mitochondrial cardiolipin may be the underlying mechanism for cardiotoxicity affecting its energy metabolism and electrostatic status.

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Bupivacaine Myotoxicity Is Mediated by Mitochondria

Cited by 163 publications

References 57 publications

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

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

Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro by inhibiting the p53-dependent mitochondrial apoptotic pathway

A cardiolipina é o alvo da cardiotoxicidade dos anestésicos locais?

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