Involvement of oxidative stress and impaired lysosomal degradation in amiodarone‐induced schwannopathy

Niimi, Naoko; Yako, Hideji; Tsukamoto, Masami; Takaku, Shizuka; Yamauchi, Junji; Kawakami, Emiko; Yanagisawa, Hiroko; Watabe, Kazuhiko; Utsunomiya, Kazunori; Sango, Kazunori

doi:10.1111/ejn.13268

Cited by 19 publications

(14 citation statements)

References 55 publications

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“…Amiodarone reacts with superoxide anions resulting in the formation of peroxynitrite, which induces lipid peroxidation leading to neurotoxicity (Lu et al, ; Niimi et al, ). MDA, which is formed by the degradation of polyunsaturated lipids by ROS, is used as a marker of oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…Toxicity usually begins with corneal deposits, microdeposits, visual disturbance and progresses slowly to the vision impairment with optic neuritis, toxic optic neuropathy and/or blindness (Miguel et al, ; Cheng et al, ; Turk et al, ). The mechanisms of amiodarone toxicity have not been defined; however, one hypothesis is that they are due to an increase in mitochondrial H 2 O 2 synthesis, which induces oxidative injury (Leeder et al, ; Serviddio et al, ; Cheng et al, ; Pomponio et al, ; Niimi et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Liao

Yan

Zhuanping

et al. 2017

British J Pharmacology

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Amiodarone is one of the most effective anti-arrhythmic drugs available, but its clinical applications are limited by toxic side effects including optic toxicity. The purpose of this study was to investigate the toxic effect of amiodarone on D407 cells (a human retinal pigmented epithelial (RPE) cell line) and the mechanisms of the protective effect of insulin-like growth factor-1 (IGF-1). EXPERIMENTAL APPROACHThe involvement of the kinases, Akt and ERK, was analysed by Western blot. Intracellular accumulation of ROS was measured using fluorophotometric quantification. A pharmacological approach with inhibitors was used to investigate the pathways involved in the protective action of IGF-1. KEY RESULTSAmiodarone concentration-dependently augmented the production of ROS, lipid peroxidation and apoptosis in D407 cells. IGF-1 time-and concentration-dependently reversed these effects of amiodarone and protected D407 cells from amiodarone-mediated toxicity. Amiodarone inhibited the pAkt but not pErk, and IGF-1 reversed this inhibitory effect of amiodarone. However, IGF-1 failed to suppress amiodarone-induced cytotoxicity in the presence of PI3K/Akt inhibitor LY294002 suggesting the direct involvement of the PI3K/Akt pathway. Furthermore, in vivo rat flash electroretinogram (FERG) recordings showed that IGF-1 reverses the amiodarone-induced decrease in a-and b-waves. The immunocytochemistry findings confirmed that vitreous IGF-1 injections promote the survival of RPE cells in rat retina treated with amiodarone. CONCLUSION AND IMPLICATIONSIGF-1 can protect RPE cells from amiodarone-mediated injury via the PI3K/Akt pathway in vivo and in vitro. IGF-1 has potential as a protective drug for the prevention and treatment of amiodarone-induced optic toxicity.Abbreviations FERG, flash electroretinogram; IGF-1, insulin-like growth factor-1; INL, inner nuclear layer; IPL, inner plexiform layer; RGCs, retinal ganglionic cells; RPE, retinal pigmented epithelium

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Liao

Yan

Zhuanping

et al. 2017

British J Pharmacology

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“…Neuronopathy caused by a platinum‐based compound such as cisplatin and oxaliplatin is characterized by neuronal death, especially dorsal root ganglia neuron (DRG) death, and is the result of mitochondrial or oxidative stress . Myelinopathy, for example, such as caused by amiodarone, is associated with damage of Schwann cells accumulated with metabolites of drugs. Since we modeled drug‐induced axonopathy with human iPSC‐derived neurons, the method in this study could not be applied to evaluate other types of drug‐induced neurotoxicity including neuronopathy and myelinopathy.…”

Section: Discussionmentioning

confidence: 99%

Modeling Drug‐Induced Neuropathy Using Human iPSCs for Predictive Toxicology

Ohara

Imamura

Morii

et al. 2017

Clin Pharma and Therapeutics

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Drugs under development can cause unpredicted toxicity in humans due to differential drug responsiveness between humans and other disease models, resulting in clinical trial failures. Human induced pluripotent stem cells (iPSCs) are expected to represent a useful tool for toxicity testing. However, among many assays, appropriate cellular assays for predicting neurotoxicity in an iPSC-based model are still uncertain. Here we generated neurons from iPSCs of Charcot-Marie-Tooth disease (CMT) patients. Some CMT patients are sensitive to anticancer drugs and present with an adverse reaction of neuropathy. We analyzed cellular phenotypes and found that mitochondria in neurites of CMT neurons were morphologically shorter and showed slower mobility compared to control. A neurosphere assay showed that treatment with drugs known to cause neuropathy caused mitochondrial aggregations in neurites with adenosine triphosphate shortage in both CMT and control neurons, although more severely in CMT. These findings suggest that the genetically susceptible model could provide a useful tool to predict drug-induced neurotoxicity.

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“…This evidence suggests that injury to Schwann cells has significance in the pathogenesis of diabetic neuropathy [6]. Apoptosis of Schwann cells has been detected in diabetic models [7][8][9][10], which could be a cause of demyelination in the peripheral nervous system [11].…”

Section: Introductionmentioning

confidence: 94%

Interleukin-10 Protects Schwann Cells against Advanced Glycation End Products-Induced Apoptosis via NF-κB Suppression

Bao²,

Men

et al. 2019

Exp Clin Endocrinol Diabetes

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Demyelination resulting from Schwann cell injury is a main pathological feature of diabetic neuropathy, and a key contributor to this process may be inflammation due to advanced glycation end products (AGEs). Therefore, protection by anti-inflammation agents is anticipated. In this study, we showed that interleukin-10 (IL-10), an anti-inflammatory cytokine, inhibits apoptosis of Schwann cells induced by AGEs in vitro. We isolated and cultured Schwann cells from rat sciatic nerves. As detected by flow cytometry, apoptosis of Schwann cells markedly increased following incubation with AGEs for 48 h. However, pretreatment with IL-10 inhibited AGE-induced apoptosis. The effect of IL-10 on NF-κB, which is a very important regulator of inflammation, was also evaluated, and results showed high levels of phospho-NF-κB and nuclear localization of NF-κB in cells incubated with AGEs but low levels of phospho-NF-κB and cytoplasmic localization in the cells incubated with IL-10, indicating the activation of NF-κB by AGEs and inhibition of NF-κB by IL-10. Moreover, incubating Schwann cells with an NF-κB inhibitor (caffeic acid phenethyl ester) for 30 min before adding AGEs mimicked IL-10, lowering the amount of reactive oxygen species and activity of caspase-3 and also decreasing apoptosis in Schwann cells. These results indicate that IL-10 may protect Schwann cells against AGE-induced apoptosis by attenuating oxidative stress via the inhibition of activation of NF-κB.

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Involvement of oxidative stress and impaired lysosomal degradation in amiodarone‐induced schwannopathy

Cited by 19 publications

References 55 publications

Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Insulin‐like growth factor‐1 activates PI3K/Akt signalling to protect human retinal pigment epithelial cells from amiodarone‐induced oxidative injury

Modeling Drug‐Induced Neuropathy Using Human iPSCs for Predictive Toxicology

Interleukin-10 Protects Schwann Cells against Advanced Glycation End Products-Induced Apoptosis via NF-κB Suppression

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