In Vitro, Inhibition of Mitogen-Activated Protein Kinase Pathways Protects Against Bupivacaine- and Ropivacaine-Induced Neurotoxicity

Lirk, Philipp; Haller, Ingrid; Colvin, Hans Peter; Lang, Leopold; Tomaselli, Bettina; Klimaschewski, Lars; Gerner, Peter

doi:10.1213/ane.0b013e318168514b

Cited by 75 publications

(73 citation statements)

References 33 publications

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“…On the other hand, it has been shown that bupivacaine, at high concentration range (1-10 mM), can cause neurotoxicity. 43,44) In a clinical setting, bupivacaine is wellknown to produce central nervous system (CNS) toxicity in patients who exceed the recommended dosage (2 mg/kg). 45,46) The dose of bupivacaine used to inhibit KA-induced seizures in our study, therefore, may be considered safe.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Bupivacaine against Kainic Acid-Induced Seizure and Neuronal Cell Death in the Rat Hippocampus

Chiu

Wang

et al. 2015

Biological & Pharmaceutical Bulletin

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The excessive release of glutamate is a critical element in the neuropathology of epilepsy, and bupivacaine, a local anesthetic agent, has been shown to inhibit the release of glutamate in rat cerebrocortical nerve terminals. This study investigated whether bupivacaine produces antiseizure and antiexcitotoxic effects using a kainic acid (KA) rat model, an animal model used for temporal lobe epilepsy, and excitotoxic neurodegeneration experiments. The results showed that administering bupivacaine (0.4 mg/kg or 2 mg/kg) intraperitoneally to rats 30 min before intraperitoneal injection of KA (15 mg/kg) increased seizure latency and reduced the seizure score. In addition, bupivacaine attenuated KA-induced hippocampal neuronal cell death, and this protective effect was accompanied by the inhibition of microglial activation and production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the hippocampus. Moreover, bupivacaine shortened the latency of escaping onto the platform in the Morris water maze learning performance test. Collectively, these data suggest that bupivacaine has therapeutic potential for treating epilepsy.

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Section: Discussionmentioning

confidence: 99%

Protective Effects of Bupivacaine against Kainic Acid-Induced Seizure and Neuronal Cell Death in the Rat Hippocampus

Chiu

Wang

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Medium was changed and cells were photographed daily with an inverted microscope (Carl Zeiss, Gottingen, Germany). We chose 24 and 48 h time points based on previous in vitro studies of LAs [10,13,19] . After image acquisition, the cells were trypsinized and stained with trypan blue (Mediatech).…”

Section: Measurement Of Cell Viabilitymentioning

confidence: 99%

“…However, we cannot completely rule out that other signaling pathway(s) may also contribute to the LAinduced myotoxicity. It has been shown that both p38 MAPK and c-Jun N-terminal kinase (JNK) pathways are involved in bupivacaine-induced neurotoxicity [13] . 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] .…”

Section: Wwwnaturecom/aps Maurice Jm Et Almentioning

confidence: 99%

“…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%

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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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“…Previous study has suggested that local anesthetics could induce apoptosis in human thyroid cancer cells, which is associated with mitogen-activated protein kinase (MAPK) pathways (13). Another report has suggested that inhibition of MAPK pathways protects against local anesthetics-induced neurotoxicity (14). However, little…”

Section: Introductionmentioning

confidence: 99%

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

Wang

Jiang

et al. 2016

J. Thorac. Dis.

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Background: A retrospective analysis of patients undergoing cancer surgery suggested that using local anesthetics could reduce cancer recurrence and improve survival rate. Previous studies have indicated that local anesthetics may induce apoptosis in several kinds of cells in vitro, but the mechanism is unclear. Methods: Cell viability was analyzed by MTS; reactive oxygen species (ROS), mitochondrial membrane potential (MMP, ∆Ψm), cell cycle distribution, and cell apoptosis assay were detected by flow cytometry; DNA damage was measured by comet assay; cell invasion and migration were observed by microscopy; The expression level of related proteins was detected by western blot assay. Results: The results indicated that lidocaine and ropivacaine could decrease viability, induce G0/G1 phase arrest and apoptosis in human non-small cell lung cancer (NSCLC) cells A549 and H520. Invasion and migration were suppressed. Western blot indicated the related apoptotic pathways proteins changed accordingly. Additionally, lidocaine and ropivacaine downregulated ∆Ψm, provoked DNA damage, upregulated ROS production and activated mitogen-activated protein kinase (MAPK) pathways in A549 and H520 cells. Conclusions:The cytotoxic effect of amide-linked local anesthetics on NSCLC cells were mainly due to apoptosis. The antitumor mechanism of lidocaine and ropivacaine may involve apoptotic pathways and MAPK pathways.

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In Vitro, Inhibition of Mitogen-Activated Protein Kinase Pathways Protects Against Bupivacaine- and Ropivacaine-Induced Neurotoxicity

Cited by 75 publications

References 33 publications

Protective Effects of Bupivacaine against Kainic Acid-Induced Seizure and Neuronal Cell Death in the Rat Hippocampus

Protective Effects of Bupivacaine against Kainic Acid-Induced Seizure and Neuronal Cell Death in the Rat Hippocampus

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

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

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