Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures

Pomponio, Giuliana; Zurich, Marie-Gabrielle; Schultz, Luise; Weiss, Dieter G.; Romanelli, L.; Gramowski-Voss, Alexandra; Consiglio, Emma Di; Testai, Emanuela

doi:10.1016/j.tiv.2015.01.012

Cited by 20 publications

(25 citation statements)

References 36 publications

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“…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%

“…The risk of adverse effects increases with dose and duration of use. Several hypotheses have been put forward to explain the toxicity of amiodarone including increased release of inflammatory mediators, mitochondrial dysfunction and free‐radical formation (Lu et al, ; Pomponio et al, ). Evidence from cell and animal studies suggests that amiodarone induces the formation of ROS; this was evaluated in a relevant in vitro model of pulmonary toxicity (Nicolescu et al, ).…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…126 Additionally, kinetics of selected drugs was studied in all three 127 organ cultures (hepatocytes, kidney and neuronal cells) and the 128 results obtained are described separately in this volume (e.g. 129 Bellwon et al, 2014;Pomponio et al, 2014). 130 In this project we aimed to develop a novel in vitro approach for 131 more comprehensive drug-induced neurotoxicity testing by pro-132 viding insight into mechanisms of neurotoxicity.…”

Section: A R T I C L E I N F O 24mentioning

confidence: 99%

Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models

Schultz

Zurich

Culot

et al. 2015

Toxicology in Vitro

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The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.

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“…Thus side effects and toxicities occur in parts of the body with this way. The most affected organs and tissues can be numbered as liver (3), lung (4), kidney (5), thyroid (6), brain (7) and ocular tissue (8). AMD is also reported as a hepatic mitochondrial toxicant that damages electron transport system by inhibiting complex I as well as b-oxidation of fatty acids.…”

Section: Introductionmentioning

confidence: 99%

Vitamin U ameliorates glycoprotein components, enzyme and tissue factor activities of amiodarone toxicity in liver

Türkyılmaz

Yanardağ

2016

Marmara Pharm J

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In this study, we aimed to investigate the protective effect of Vitamin U (Vit U) on amiodarone (AMD)-induced hepatotoxicity. Male Sprague-Dawley rats were randomly divided into four groups. Group I was control animals receiving corn oil for 7 days, Group II consisted of animals receiving Vit U (50 mg/kg) for 7 days, Group III consisted of animals receiving AMD (100 mg/kg) for 7 days and Group IV consisted of animals given AMD and Vit U (in same dose and time). AMD and Vit U were administered to rats by gavage. On the 8th day, all the animals fasted overnight were sacrificed. Blood and liver tissue samples were taken from animals. Serum total cholesterol levels and liver gamma glutamyl transferase (transpeptidase) adenosine deaminase and tissue factor activities, liver glycoprotein component level such as fucose, hexose and hexosamine were determined. All the parameters were found to be increased in AMD group as compared to control group. Administration of Vit U reversed these effects in AMD group. According to these results, we can conclude that Vit U can prevent AMD-induced liver injury.

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Amiodarone biokinetics, the formation of its major oxidative metabolite and neurotoxicity after acute and repeated exposure of brain cell cultures

Cited by 20 publications

References 36 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

Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models

Vitamin U ameliorates glycoprotein components, enzyme and tissue factor activities of amiodarone toxicity in liver

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