Possible Mechanism of Irreversible Nerve Injury Caused by Local Anesthetics

Kitagawa, Norihito; Oda, Mayuko; Totoki, Tadahide

doi:10.1097/00000542-200404000-00029

Cited by 76 publications

(12 citation statements)

References 26 publications

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“…T-type calcium channels may be involved in bupivacaine neurotoxicity34. Furthermore, LAs increased mitochondrial reactive oxygen species (ROS), caused mitochondrial dysfunction (mitochondrial DNA damage, a decrease in adenosine triphosphate and mitochondrial protein levels), dysregulated mitochondrial Ca 2+ signalling, elevated mitochondrial oxidant stress, and caused nerve membrane solubilization resulting in irreversible neural injury and apoptosis3536. Bupivacaine exerts its neurotoxic effects in SH-SY5Y cells by generating excess ROS and activating autophagy via regulation of the PI3K (i.e., PIK3CB and PIK3R2) signalling pathway24.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine

Zhao

et al. 2017

Sci Rep

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Local anaesthetics (LAs) may lead to neurological complications, but the underlying mechanism is still unclear. Many neurotoxicity research studies have examined different LAs, but none have comprehensively explored the distinct mechanisms of neurotoxicity caused by amide- (bupivacaine) and ester- (procaine) type LAs. Here, based on a CCK8 assay, LDH assay, Rhod-2-AM and JC-1 staining, 2′,7′-dichlorohy-drofluorescein diacetate and dihydroethidium probes, an alkaline comet assay, and apoptosis assay, we show that both bupivacaine and procaine significantly induce mitochondrial calcium overload and a decline in the mitochondrial membrane potential as well as overproduction of ROS, DNA damage and apoptosis (P < 0.05). There were no significant differences in mitochondrial injury and apoptosis between the bupivacaine and procaine subgroups (P > 0.05). However, to our surprise, the superoxide anionic level after treatment with bupivacaine, which leads to more severe DNA damage, was higher than the level after treatment with procaine, while procaine produced more peroxidation than bupivacaine. Some of these results were also affirmed in dorsal root ganglia neurons of C57 mice. The differences in the superoxidation and peroxidation induced by these agents suggest that different types of LAs may cause neurotoxicity via different pathways. We can target more accurate treatment based on their different mechanisms of neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine

Zhao

et al. 2017

Sci Rep

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“…Our main purpose was to study how these drugs interleave the membrane, since in water this conformation occurs due to the high amphiphilicity of the charged form of LAs [17,42]. One of the main reasons that led us to simulate only one drug molecule in the box is that, due to the experimental observed interaction between them [43], simulation artefacts could mislead the results. The concentration effect could be studied through larger membrane patches, whereas, with higher drugs concentration, we could study the effect of the drugs on the pressure developed by the membrane in the wall of the simulation box.…”

Section: Molecular Physics 1439mentioning

confidence: 99%

Molecular dynamics study of biomembrane/local anesthetics interactions

et al. 2009

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It is still controversial how local anesthetics (LAs) act upon the nervous system and how the membrane contributes to this process, since probably the most important active site of the LAs is located in the sodium channels, a trans-membrane protein. An important role of the bio-membrane would be the stabilization and orientation of local anesthetics molecules, reducing their translational and rotational degrees of freedom, which could reinforce the mechanisms which interrupt the nervous impulse. This study aims to perform a computational analysis of the LAs behaviour in the membrane, and the effect of the water/membrane interface on their stabilization and orientation. Analysis by molecular dynamics (MD) showed that the charged form of these drugs are oriented at the interface, while the neutral form can easily cross the interface, entering the membrane, in agreement with the most recent experimental results in the literature. In contrast, it is here suggested that benzocaine (BZC), which exists only in its uncharged form in physiological media, behaves like the charged anesthetics, remaining stabilized and oriented at the interface. This could explain the similar anesthetic effect of BZC and the charged forms of tetracaine (TTC) and lidocaine (LDC).

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“…The microfilament is composed of actin that undergoes an enzymatic polymerization (14). Although Kitagawa et al (16) reported that neurons are irreversibly injured by the detergent properties of local anesthetics, delayed nerve growth in the present study was probably independent of the membrane lysis action of local anesthetics because the detergent properties of local anesthetics become apparent only when the concentration of local anesthetics is larger than 34.5 mM. The concentration of tetracaine in the present study was very small (Ͻ20 M), and growth cone morphology was mostly intact, making the above explanation by Kitagawa et al (16), with regard to neuronal growth retardation, unlikely in this study.…”

Section: Discussionmentioning

confidence: 99%

Tetracaine at a Small Concentration Delayed Nerve Growth Without Destroying Neurites and Growth Cones

Sekimoto

Saito²,

Goto³

2006

Anesthesia & Analgesia

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Local anesthetics have direct neurotoxicity and induce growth cone collapse when applied to neurons at large concentrations. However, the effects of prolonged exposure to local anesthetics at a small concentration have never been studied. We examined whether neurite growth was slowed by tetracaine at small concentrations in chick embryo dorsal root ganglions. The effects of tetracaine were examined microscopically and by a neurite growth rate assay, quantitative morphologic assay, growth cone collapse assay, and Western blot assay. Neurite growth 24 and 48 h after application was delayed significantly when tetracaine was applied at a concentration larger than 5 microM. Filopodia of growth cones retracted, and their number was significantly decreased 24 and 48 h after the application of 10 and 20 microM of tetracaine. The quantity of actin in cell bodies increased, contrary to the effect on neurites and growth cones, where actin decreased 48 h after the application of 5, 10, and 20 microM of tetracaine. In conclusion, continuous exposure to tetracaine at small concentrations delayed neurite growth, reduced the number of filopodia, and decreased actin content.

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Possible Mechanism of Irreversible Nerve Injury Caused by Local Anesthetics

Cited by 76 publications

References 26 publications

Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine

Neurotoxicity Comparison of Two Types of Local Anaesthetics: Amide-Bupivacaine versus Ester-Procaine

Molecular dynamics study of biomembrane/local anesthetics interactions

Tetracaine at a Small Concentration Delayed Nerve Growth Without Destroying Neurites and Growth Cones

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