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  Age and Sex Differences in the Effects of the Immunosuppressants Cyclosporine, Sirolimus and Everolimus on Rat Brain Metabolism

Gottschalk, S., Cummins, C., Leibfritz, D., Christians, U., Benet, L., & Serkova, N. (2011). Age and Sex Differences in the Effects of the Immunosuppressants Cyclosporine, Sirolimus and Everolimus on Rat Brain Metabolism. NeuroToxicology, 32(1), 50-57. doi:10.1016/j.neuro.2010.10.006.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0013-BCBA-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-BCCD-5
Genre: Journal Article

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Gottschalk, S1, 2, Author              
Cummins, CL, Author
Leibfritz , D, Author
Christians, U, Author
Benet, LZ, Author
Serkova, NJ, Author
Affiliations:
1Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497796              
2Max Planck Institute for Biological Cybernetics, Max Planck Society, Spemannstrasse 38, 72076 Tübingen, DE, ou_1497794              

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 Abstract: Application of the widely used immunosuppressant (ISS) cyclosporine (CsA) is severely limited by a number of serious side-effects such as kidney- and neurotoxicity. As we have shown before, CsA exhibits metabolic toxicity in brain-models. The macrolide ISSs sirolimus (SRL) and everolimus (RAD) are capable of modulating these CsA-induced effects. It was our aim to study the age-dependent metabolic changes in the rat brain after ISS-treatment and the possible role of the blood-brain-barrier in modulation of CsA metabolic toxicity. Young and adult rats were treated orally with one ISS alone or in combination with CsA for six days. Metabolic changes were assessed by nuclear magnetic resonance (NMR) spectroscopy of brain extracts as toxicodynamic endpoints. Brain P-glycoprotein (P-gp) and ISS concentrations were determined as pharmacokinetic endpoints. Young rats were more susceptible to CsA-induced inhibition of the Krebs cycle (glutamate: 78 of controls, glutamine: 82, GABA: 71 in young vs. 85, 89, 92 in adult rats). Increased glycolysis after CsA-treatment was sufficient to maintain the energy state at control levels in adult brains, but not in the young rat brains (phosphocreatine: 35). Tissue concentrations of CsA and SRL within the brain of young rats were three-fold higher, while concentrations of P-gp were three-fold higher in adult rat brains. Our results suggest that age-dependent differences in the blood-brain barrier led to increased ISS brain concentrations and hence inhibition of brain energy metabolism.

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 Dates: 2011-01
 Publication Status: Published in print
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 Identifiers: DOI: 10.1016/j.neuro.2010.10.006
BibTex Citekey: 6872
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Title: NeuroToxicology
Source Genre: Journal
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Pages: - Volume / Issue: 32 (1) Sequence Number: - Start / End Page: 50 - 57 Identifier: -