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Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism

Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism

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Prüfsumme: MD5:d9c41d68e0722d68952934c8d565f803

EFREMOVA, Liudmila, Stefan SCHILDKNECHT, Martina ADAM, Regina PAPE, Simon GUTBIER, Benjamin HANF, Alexander BÜRKLE, Marcel LEIST, 2015. Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism. In: British Journal of Pharmacology. 172(16), pp. 4119-4132. ISSN 0007-1188. eISSN 1476-5381. Available under: doi: 10.1111/bph.13193

@article{Efremova2015-08Preve-31073, title={Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism}, year={2015}, doi={10.1111/bph.13193}, number={16}, volume={172}, issn={0007-1188}, journal={British Journal of Pharmacology}, pages={4119--4132}, author={Efremova, Liudmila and Schildknecht, Stefan and Adam, Martina and Pape, Regina and Gutbier, Simon and Hanf, Benjamin and Bürkle, Alexander and Leist, Marcel} }

eng Gutbier, Simon Adam, Martina Efremova, Liudmila Gutbier, Simon Leist, Marcel Bürkle, Alexander Leist, Marcel Efremova, Liudmila Schildknecht, Stefan Background and purpose <br /> Few neuropharmacological model systems use human neurons. Moreover, available test systems rarely reflect functional roles of co-cultured glial cells. There is no human in vitro counterpart of the widely used 1-methyl-4-phenyl-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. <br /><br />Experimental Approach <br />We generated such a model by growing an intricate network of human dopaminergic neurons on a dense layer of astrocytes. In these co-cultures, MPTP was metabolized to 1-methyl-4-phenyl-pyridinium (MPP<sup>+</sup>) by the glial cells, and the toxic metabolite was taken up through the dopamine transporter into neurons. Cell viability was measured biochemically and by quantitative neurite imaging, siRNA techniques were also used. <br /><br />Key Results <br /> We initially characterized the activation of PARP. As in mouse models, MPTP exposure induced (poly-ADP-ribose) synthesis and neurodegeneration was blocked by PARP inhibitors. Several different putative neuroprotectants were then compared in mono-cultures and co-cultures. Rho kinase inhibitors worked in both models; CEP1347, ascorbic acid or a caspase inhibitor protected mono-cultures from MPP<sup>+</sup> toxicity, but did not protect co-cultures, when used alone or in combination. Application of GSSG prevented degeneration in co-cultures, but not in mono-cultures. The surprisingly different pharmacological profiles of the models suggest that the presence of glial cells, and the in situ generation of the toxic metabolite MPP<sup>+</sup> within the layered cultures played an important role in neuroprotection.<br /><br />Conclusions and Implications<br /> Our new model system is a closer model of human brain tissue than conventional cultures. Its use for screening of candidate neuroprotectants may increase the predictiveness of a test battery. Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism Hanf, Benjamin 2015-06-01T09:41:37Z Pape, Regina 2015-08 Bürkle, Alexander Hanf, Benjamin Pape, Regina 2015-06-01T09:41:37Z Schildknecht, Stefan Adam, Martina

Dateiabrufe seit 01.06.2015 (Informationen über die Zugriffsstatistik)

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