Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood–brain barrier

Bellwon, Patricia; Culot, Maxime; Wilmes, Anja; Schmidt, Tobias; Zurich, Marie-Gabrielle; Schultz, Luise; Schmal, Olga; Gramowski-Voss, Alexandra; Weiss, Dieter G.; Jennings, Paul; Bal‐Price, Anna; Testai, Emanuela; Dekant, W.

doi:10.1016/j.tiv.2015.01.003

Cited by 21 publications

(14 citation statements)

References 65 publications

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“…CNIs are also known to cause arterial hypertension and diabetes which eventually lead to cerebral damage by premature atherosclerosis and microangiopathy . Another important finding was made by Bellwon et al who assumed that CNIs have the capacity to alter the blood‐brain barrier extrusion capacity which might impair neuronal function . The results of these studies implicate the strong need for clinical studies addressing the effect of long‐term CNI therapy on brain function.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning neurological side effects of CNI therapy data is predominantly available for the first few weeks after liver transplantation indicating CNI‐induced neurotoxicity . The capability of ciclosporin to cross the blood‐brain‐barrier was shown in vitro . However, only sparse data are available addressing the long‐term effect of CNI therapy on brain function, structure and metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation

Schmitz

Pflugrad

Tryc

et al. 2019

Aliment Pharmacol Ther

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Background: Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism.Aims: To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation.Methods: Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10 years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents.The MRS results were correlated with psychometric data assessing cognitive function. Results:Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209 ± 0.012 vs 0.222 ± 0.010; P < 0.001) and a significant increase in PCr (0.344 ± 0.026 vs 0.321 ± 0.017; P < 0.001) compared to controls. Myo-Inositol in the CNI free group (2.719 ± 0.549 institutional unit [iu]) was significantly lower compared to controls (3.181 ± 0.425 iu; P = 0.02), patients on low-dose (3.130 ± 0.513 iu; P < 0.05) and standard-dose CNI therapy (3.207 ± 0.632 iu; P < 0.02). Glutamate and glutamine levels correlated negatively with cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status Total Scale: R = −0.362, P = 0.029).Conclusion: Long-term CNI therapy after liver transplantation might be associated with alterations of brain metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation

Schmitz

Pflugrad

Tryc

et al. 2019

Aliment Pharmacol Ther

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“…Moreover, once tacrolimus enters the brain, it is eliminated slowly by binding to FKBP [109]. In an in vitro model, CsA inhibits calcineurin in the brain, even at concentrations as low as 200 nM, in a relatively short time frame and this inhibitory effect is sustained during drug administration [93]. With the exception of calcineurin inhibition by the tacrolimus-FKBP complex, the exact mechanism of neurotoxicity is not completely elucidated.…”

Section: Cnismentioning

confidence: 99%

“…and significant intracellular CNI uptake, thus increasing the toxicity of other drugs administered at the same time [93]. Metabolites of CNIs may also be neurotoxic, even though they are usually not assessed in clinical practice.…”

Section: Cnismentioning

confidence: 99%

Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities

Zhang¹,

Egashira²,

Masuda³

2019

Preprint

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Although transplantation procedures have been developed for patients with end-stagec hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents, such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity is commonly occurred in clinical situations, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms whereby CNIs cause neurotoxicity include: increasing the permeability or injury of the blood-brain barrier, alterations of mitochondrial function, and alterations in electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures; mycophenolate mofetil induces depression and headache; methotrexate affects the central nervous system; mouse monoclonal immunoglobulin G2 antibody against cluster of differentiation 3 also induces headache; and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms have greatly reduced neurotoxic events. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, using drugs to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize the recent topics on the mechanisms of neurotoxicity of immunosuppressive drugs. In addition, some information about neuroprotective effects of several immunosuppressants are also discussed.

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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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Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood–brain barrier

Cited by 21 publications

References 65 publications

Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation

Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation

Recent Topics on the Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities

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

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