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Moreover, available test systems rarely reflect functional roles of co\u2010cultured glial cells. There is no human<jats:italic>in vitro<\/jats:italic>counterpart of the widely used 1\u2010methyl\u20104\u2010phenyl\u2010tetrahydropyridine (<jats:styled-content style=\"fixed-case\">MPTP<\/jats:styled-content>) mouse model of Parkinson's disease<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We generated such a model by growing an intricate network of human dopaminergic neurons on a dense layer of astrocytes. In these co\u2010cultures,<jats:styled-content style=\"fixed-case\">MPTP<\/jats:styled-content>was metabolized to 1\u2010methyl\u20104\u2010phenyl\u2010pyridinium (<jats:styled-content style=\"fixed-case\">MPP<\/jats:styled-content><jats:sup>+<\/jats: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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We initially characterized the activation of<jats:styled-content style=\"fixed-case\">PARP<\/jats:styled-content>. As in mouse models,<jats:styled-content style=\"fixed-case\">MPTP<\/jats:styled-content>exposure induced (poly\u2010<jats:styled-content style=\"fixed-case\">ADP<\/jats:styled-content>\u2010ribose) synthesis and neurodegeneration was blocked by<jats:styled-content style=\"fixed-case\">PARP<\/jats:styled-content>inhibitors. Several different putative neuroprotectants were then compared in mono\u2010cultures and co\u2010cultures. Rho kinase inhibitors worked in both models;<jats:styled-content style=\"fixed-case\">CEP<\/jats:styled-content>1347, ascorbic acid or a caspase inhibitor protected mono\u2010cultures from<jats:styled-content style=\"fixed-case\">MPP<\/jats:styled-content><jats:sup>+<\/jats:sup>toxicity, but did not protect co\u2010cultures, when used alone or in combination. Application of<jats:styled-content style=\"fixed-case\">GSSG<\/jats:styled-content>prevented degeneration in co\u2010cultures, but not in mono\u2010cultures. The surprisingly different pharmacological profiles of the models suggest that the presence of glial cells, and the<jats:italic>in situ<\/jats:italic>generation of the toxic metabolite<jats:styled-content style=\"fixed-case\">MPP<\/jats:styled-content><jats:sup>+<\/jats:sup>within the layered cultures played an important role in neuroprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13193","type":"journal-article","created":{"date-parts":[[2015,5,19]],"date-time":"2015-05-19T03:53:06Z","timestamp":1432007586000},"page":"4119-4132","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Prevention of the degeneration of human dopaminergic neurons in an astrocyte co\u2010culture system allowing endogenous drug metabolism"],"prefix":"10.1111","volume":"172","author":[{"given":"Liudmila","family":"Efremova","sequence":"first","affiliation":[{"name":"Doerenkamp\u2010Zbinden Chair for In Vitro Toxicology and Biomedicine University of Konstanz Konstanz Germany"},{"name":"Research Training Group 1331 (RTG1331) University of Konstanz Konstanz 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