Effect of tacrolimus on energy metabolism in human umbilical endothelial cells

Illsinger, Sabine; Göken, Catrin; Brockmann, Matthias; Thiemann, Inga; Bednarczyk, Jolanthe; Schmidt, Karl‐Heinz; Lücke, Thomas; Hoy, Ludwig; Janzen, Nils

doi:10.12659/aot.881868

Cited by 21 publications

(14 citation statements)

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“…Furthermore, tacrolimus therapy is associated with neurological complications in the first few weeks after transplantation [13] and these are expected in the long-term as well. Several possible pathomechanisms are discussed: Tacrolimus induced cardiovascular risk factors [12] enhance atherosclerosis and microangiopathy which may lead to cerebrovascular events and subsequently impaired brain function, tacrolimus might cause neurodegeneration by inhibiting the cerebral immune system [15] and tacrolimus might impair the cerebral energy metabolism [14].…”

Section: Discussionmentioning

confidence: 99%

“…Another tacrolimus associated pathomechanism underlying cognitive dysfunction in patients after KT is the possible impairment of the cerebral energy metabolism. Illsinger and colleagues showed in vitro that clinically relevant tacrolimus concentrations impair the mitochondrial energy metabolism in human umbilical endothelial cells [14]. Furthermore, tacrolimus induced alterations of mitochondrial function was described in human cell lines [30].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, long-term neurological side effects of CNI therapy have hardly been explored although central nervous system toxicity is one of the most important short term side effects of CNIs after transplantation [13]. Long-term CNI therapy could add to the occurrence of cognitive dysfunction after KT by inducing cerebrovascular atherosclerosis and microangiopathy [12], chronic impairment of the cerebral mitochondrial energy metabolism [14] and/or an alteration of the cerebral immune system with consecutive neurodegeneration [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation

et al. 2020

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Background About 50% of the patients 5-7 years after kidney transplantation show impairment of memory, attention and executive function. Tacrolimus frequently induces neurological complications in the first few weeks after transplantation. Furthermore, tacrolimus treatment is associated with impaired cognitive function in the long-term in patients after liver transplantation. We hypothesize that long-term tacrolimus therapy is associated with cognitive dysfunction and alterations of brain structure and metabolism in patients after kidney transplantation. Methods Twenty-one patients 10 years after kidney transplantation underwent cognitive testing, magnetic resonance imaging and whole brain 31-phosphor magnetic resonance spectroscopy for the assessment of brain function, structure and energy metabolism. Using a cross-sectional study design the results were compared to those of patients 1 (n = 11) and 5 years (n = 10) after kidney transplantation, and healthy controls (n = 17). To further analyze the share of transplantation, tacrolimus therapy and kidney dysfunction on the results patients after liver transplantation (n = 9) were selected as a patient control group.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation

et al. 2020

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“…In human cell lines tacrolimus induced a decrease in oxygen consumption and a reduction of deoxyribonucleic acid encoded protein synthesis in mitochondria . Illsinger et al showed a negative effect of ciclosporin and tacrolimus on the mitochondrial energy metabolism in human endothelial cells, derived from the umbilical cord . Serkova et al have shown that ciclosporin significantly decreases concentration of high‐energy phosphates in rat brain slices as well as in rat brain in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…These studies also suggest a negative effect of long‐term CNI therapy upon brain structure and function . Currently several possible mechanisms of CNI‐induced alteration of the brain are discussed: premature CNI induced atherosclerosis and microangiopathy with consecutive structural brain alterations, impairment of the cerebral immune system, impairment of the mitochondrial energy metabolism and alteration of mitochondrial function …”

Section: Introductionmentioning

confidence: 97%

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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Hepatic Encephalopathy Is Reversible in the Long Term After Liver Transplantation

et al. 2019

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Cognitive dysfunction caused by hepatic encephalopathy (HE) improves within the first year after liver transplantation (LT). However, cognitive restitution seems to be incomplete in a subset of patients and after LT a new‐onset cognitive decline was described. Data about the longterm development of cognitive function after liver transplantation (LT) are sparse. This prospective study analyzed whether a history of hepatic encephalopathy (HE) before LT had an impact on the longterm outcome of cognitive function after LT and if patients who underwent LT 5 years earlier showed worse cognitive function than healthy controls. The cognitive function of 34 patients was assessed before LT and at 1 year and 5 years after LT by psychometric tests, including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the portosystemic encephalopathy syndrome test, which provides the psychometric hepatic encephalopathy score (PHES). Furthermore, patients completed surveys to assess health‐related quality of life (HRQOL). An 22 additional patients were included after LT. Patients were subdivided by having a history of HE before LT. The control group consisted of 55 healthy patients adjusted for age and education. Before LT, patients performed significantly worse than controls in the psychometric tests: RBANS Total Scale (TS), mean ± standard deviation (SD), 92.6 ± 13.3 versus 99.9 ± 12.0, P = 0.01; and PHES, median (interquartile range [IQR]), 0 (−3 to 1) versus 1 (0‐2), P < 0.001. At 1 year after LT, patients with a history of HE still showed cognitive impairment compared with controls: RBANS TS, mean ± SD, 89.8 ± 15.1 versus 99.9 ± 12.0, P < 0.01; and PHES, median (IQR), 0 (−2 to 1.25) versus 1 (0‐2), P = 0.03. At 5 years after LT, patients with and without a history of HE showed normal cognitive function and improved HRQOL. In conclusion, HE‐associated cognitive impairment seems to be reversible within 5 years after LT.

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Effect of tacrolimus on energy metabolism in human umbilical endothelial cells

Cited by 21 publications

References 0 publications

Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation

Brain function and metabolism in patients with long-term tacrolimus therapy after kidney transplantation in comparison to patients after liver transplantation

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

Hepatic Encephalopathy Is Reversible in the Long Term After Liver Transplantation

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