Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron

Onizuka, Shin; Tamura, Ryuji; Yonaha, Tetsu; Oda, Nobuko; Kawasaki, Yuko; Shirasaka, Tetsuro; Shiraishi, Seiji; Tsuneyoshi, Isao

doi:10.1007/s00540-011-1260-y

Cited by 15 publications

(13 citation statements)

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“…Lidocaine has been indicated to induce morphological changes such as cell axon collapse and cell swelling (Kasaba et al 2003;Onizuka et al 2005) and to promote apoptosis through the mitochondrial pathway (Johnson et al 2004;Onizuka et al 2010Onizuka et al , 2011Werdehausen et al 2007) and even necrosis (Lawrence et al 1966;Onizuka et al 2012;Yagiela et al 1982). And the promotion to apoptosis or necrosis is not associated with the block of voltage-gated sodium channel, which is the main target of lidocaine, for its anesthetic effect.…”

Section: Introductionmentioning

confidence: 99%

“…However, it has shown to be neurotoxic, particularly to patients who are subject to spinal anesthesia with this agent (Lambert et al 1994;Rigler et al 1991) or subject to an overdose intravascular administration . The major side effects of lidocaine develop in the central nervous system, gastrointestinal tract, and cardiovascular system, including syndromes such as drowsiness, dizziness, hypotension, and cardiovascular collapse (Onizuka et al 2012). In addition, lidocaine causes damage to the liver and to articular chondrocytes (Werdehausen et al 2009).…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

Han

2014

J Mol Neurosci

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Lidocaine has been indicated to promote apoptosis and to promote endoplasmic reticulum (ER) stress. However, the mechanism underlining ER stress-mediated apoptosis is unclear. In the present study, we investigated the promotion to ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Firstly, we confirmed that lidocaine treatment induced apoptosis in SH-SY5Y cells, time-dependently and dose-dependently, via MTT cell viability assay and annexin V/FITC apoptosis detection with a FACScan flow cytometer. And the anti-apoptosis Bcl-2 and Bcl-xL were downregulated, whereas the apoptosis-executive caspase 3 was promoted through Western blot assay and caspase 3 activity assay. Moreover, the ER stress-associated binding immunoglobulin protein (BiP), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP) were also upregulated at both mRNA and protein levels by lidocaine treatment. On the other hand, downregulation of the ER stress-associated BiP by RNAi method not only blocked the lidocaine-promoted ER stress but also attenuated the lidocaine-induced SH-SY5Y cell apoptosis. In conclusion, the present study confirmed the involvement of ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Our study provides a better understanding on the mechanism of lidocaine's neurovirulence.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

Han

2014

J Mol Neurosci

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“…Although various VGSC mutations were found to alter the susceptibility to local anaesthetics (Onizuka et al . ), lidocaine was also reported to affect other membrane currents, such as voltage‐gated K + currents (Komai & McDowell, ; Panigel & Cook, ) and the inward rectifier currents (Raymond, ). This apparent lack of specificity of lidocaine, in contrast to, for example, the VGSC block caused by toxins (Stevens et al .…”

Section: Introductionmentioning

confidence: 99%

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

Moldovan

Lange

Aachmann-Andersen

et al. 2014

The Journal of Physiology

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Key pointsr We tested the recovery of motor axon conduction and multiple measures of excitability by 'threshold-tracking' after ultrasound-guided distal median nerve regional anaesthesia by lidocaine.r Lidocaine caused a transient conduction failure that recovered completely by 3 h, whereas excitability recovered only partially by 6 h and fully by 24 h.r The up to 7-fold increase in threshold after complete recovery of conduction was associated with excitability changes that could only partially be explained by block of the voltage-gated Na + channel (VGSC).r Mathematical modelling indicated that, apart from a reduction in the number of functioning VGSCs, lidocaine also caused a decrease of passive membrane resistance and an increase of capacitance.r Our data suggest that lidocaine, even at clinical 'sub-blocking' concentrations, could cause a reversible structural impairment of the axolemma. AbstractThe local anaesthetic lidocaine is known to block voltage-gated Na + channels (VGSCs), although at high concentration it was also reported to block other ion channel currents as well as to alter lipid membranes. The aim of this study was to investigate whether the clinical regional anaesthetic action of lidocaine could be accounted for solely by the block of VGSCs or whether other mechanisms are also relevant. We tested the recovery of motor axon conduction and multiple measures of excitability by 'threshold-tracking' after ultrasound-guided distal median nerve regional anaesthesia in 13 healthy volunteers. Lidocaine caused rapid complete motor axon conduction block localized at the wrist. Within 3 h, the force of the abductor pollicis brevis muscle and median motor nerve conduction studies returned to normal. In contrast, the excitability of the motor axons at the wrist remained markedly impaired as indicated by a 7-fold shift of the stimulus-response curves to higher currents with partial recovery by 6 h and full recovery by 24 h. The strength-duration properties were abnormal with markedly increased rheobase and reduced strength-duration time constant. The changes in threshold during electrotonus, especially during depolarization, were markedly reduced. The recovery cycle showed increased refractoriness and reduced superexcitability. The excitability changes were only partly similar to those previously observed after poisoning with the VGSC blocker tetrodotoxin. Assuming an unaltered ion-channel gating, modelling indicated that, apart from up to a 4-fold reduction in the number of functioning VGSCs, lidocaine also caused a decrease of passive membrane resistance and an increase of capacitance. Our data suggest that the lidocaine effects, even at clinical 'sub-blocking' concentrations, could reflect, at least in part, a reversible structural impairment of the axolemma.

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“…However, gastropod nervous systems such as those of Aplysia (e.g., Chalazonitis and Takeuchi, 1966; Chalazonitis et al, 1966; Ascher et al, 1976; Just and Hoyer, 1977; Marty, 1978; Cote and Wilson, 1980; Arimura and Ikemoto, 1986; Ikemoto, 1986; Ikemoto et al, 1988; Komatsu et al, 1996; Winegar et al, 1996; Winegar and Yost, 1998), Helix (e.g., Chalazonitis et al, 1966; Chalazonitis, 1967; Judge and Norman, 1982; Akaike et al, 1982) and Lymnaea provide us with excellent models for studies on anesthesia given their large identifiable nerve cells and well-studied behavioral repertoires (e.g., Kandel, 1976; Benjamin, 2012; Winlow and Polese, 2014). Since the middle 1980s a substantial body of work has accrued on the pond-snail Lymnaea stagnalis (L.) (e.g., Cruickshank et al, 1985b,c; Franks and Lieb, 1988; Girdlestone et al, 1989a,b; Winlow et al, 1992, 1998; McKenzie et al, 1995; Spencer et al, 1995, 1996; Lopes et al, 1998; Hamakawa et al, 1999; Onizuka et al, 2005b; Browning and Lukowiak, 2008; Onizuka et al, 2008a,b, 2012a,b; Yar and Winlow, 2016; Qazzaz and Winlow, 2017; Armstrong et al, 2018) and on related molluscs ( Euhadra - Onozuka et al, 1993; Bulla – Khalsa et al, 1995; Achatina fullica – Lin and Tsai, 2005; Lin et al, 2010; Tritonia diomedea – Wyeth et al, 2009; Elysia viridis – Cruz et al, 2012). Cephalopod molluscs are of course more complex animals than gastropods and have not easily lent themselves to the sorts of study outlined above.…”

Section: Actions Of Clinical Anesthetics On Gastropod Molluscsmentioning

confidence: 99%

“…Furthermore, Onozuka et al (1993) have demonstrated that lidocaine suppression of Na + current in Euhadra neurons is mediated by cyclic AMP dependent protein phosphorylation. Clinical doses of lidocaine have been found to cause necrosis and apoptosis in the cultured Lymnaea LPeD1 neuron with a dose-dependent decrease in membrane resistance and an increase in membrane capacitance (Onizuka et al, 2012b). …”

Section: Actions Of Clinical Anesthetics On Gastropod Molluscsmentioning

confidence: 99%

Sense and Insensibility – An Appraisal of the Effects of Clinical Anesthetics on Gastropod and Cephalopod Molluscs as a Step to Improved Welfare of Cephalopods

et al. 2018

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Recent progress in animal welfare legislation stresses the need to treat cephalopod molluscs, such as Octopus vulgaris, humanely, to have regard for their wellbeing and to reduce their pain and suffering resulting from experimental procedures. Thus, appropriate measures for their sedation and analgesia are being introduced. Clinical anesthetics are renowned for their ability to produce unconsciousness in vertebrate species, but their exact mechanisms of action still elude investigators. In vertebrates it can prove difficult to specify the differences of response of particular neuron types given the multiplicity of neurons in the CNS. However, gastropod molluscs such as Aplysia, Lymnaea, or Helix, with their large uniquely identifiable nerve cells, make studies on the cellular, subcellular, network and behavioral actions of anesthetics much more feasible, particularly as identified cells may also be studied in culture, isolated from the rest of the nervous system. To date, the sorts of study outlined above have never been performed on cephalopods in the same way as on gastropods. However, criteria previously applied to gastropods and vertebrates have proved successful in developing a method for humanely anesthetizing Octopus with clinical doses of isoflurane, i.e., changes in respiratory rate, color pattern and withdrawal responses. However, in the long term, further refinements will be needed, including recordings from the CNS of intact animals in the presence of a variety of different anesthetic agents and their adjuvants. Clues as to their likely responsiveness to other appropriate anesthetic agents and muscle relaxants can be gained from background studies on gastropods such as Lymnaea, given their evolutionary history.

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Clinical dose of lidocaine destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron

Abstract: A clinical dose of lidocaine greater than 5 mM destroys the cell membrane and induces both necrosis and apoptosis in an identified Lymnaea neuron.

Cited by 15 publications

References 46 publications

Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

Endoplasmic Reticulum Stress Is Involved in the Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells

Transient impairment of the axolemma following regional anaesthesia by lidocaine in humans

Sense and Insensibility – An Appraisal of the Effects of Clinical Anesthetics on Gastropod and Cephalopod Molluscs as a Step to Improved Welfare of Cephalopods

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