Summary
The complexity of the nervous systems has to some extent inhibited the discovery, validation and application of in vitro models to neurotoxicity testing as well as the regulatory recognition of their potential usefulness in compound development. The availability of in vitro organotypic models for brain together with other systems for detecting peripheral neuropathy in vitro has, however, now facilitated recommendations for tiered systems and batteries incorporating such models as key elements. Some of the long-standing questions such as „What about the blood-brain-barrier and metabolic activation?“ can also begin to be addressed as the access to co-cultures of endothelial and liver cells with e.g. organotypic reaggregate cultures becomes available. This, together with identification of more salient in vitro endpoints with clinical relevance and better human in vivo neurotoxicological databases, will hopefully expedite regulatory acceptance of the in vitro approach, facilitate interdisciplinary prevalidation and validation work, and hopefully direct higher-level research funding to this important area of cellular toxicology.
Zusammenfassung
Der komplexe Aufbau des Nervensystems hat bis zu einem gewissen Grad die Entdeckung, die Validierung and Anwendung von in vitro-Modellen bei neurotoxikologischen Tests sowie die Anerkennung ihrer potentiellen Verwendbarkeit im Rahmen der Medikamentenentwicklung gehemmt.
Die Verfügbarkeit von organspezifischen in vitro-Modellen des Gehirns in Verbindung mit anderen Testsystemen zur Erkennung einer peripheren Neuropathie in vitro hat die Empfehlung für verknüpfte Testsysteme und -anordnungen, die solche Modelle als Schlüsselelemente beinhalten, erleichtert.
Einige der schon lange bestehenden Fragen, wie z.B.: „ Was ist mit der Blut-Hirn-Schranke und der metabolischen Aktivität?“, können jetzt mit der Erschließung der Cokulturen von Endothel- und Leberzellen mit z.B. organspezifischen reaggregierten Kulturen angegangen werden.
Dies wird, in Verbindung mit der Identifikation von weiteren hervortretenden in vitro-Endpunkten mit klinischer Relevanz und besserer neurotoxikologischer in vivo-Datenbasis im Humanbereich, hoffentlich eine akkzeptanz der in vitro-Herangehensweise und die Erleichterung von Prevalidierung und Validierung sowie eine stärkere Unterstützung dieses wichtigen Bereichs der zellulären Toxikologie mit sich bringen.
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Abbreviations
- CNS:
-
Central Nervous System
- PNS:
-
Periphral Nervous System
- EPA:
-
Environmental Protection Agency
- FDA:
-
Food and Drug Administration (USA)
- ECVAM:
-
European Centre for the Validation of Alternative Methods
- FRAME:
-
Fund for the Replacement of Animals in Medical Experiments (UK)
- BTS:
-
British Toxicology Society
- CMR:
-
Centre for Medicines Research (UK)
- OPIDN:
-
Organophosphate Induced Delayed Neuropathy
- ATLA:
-
Alternatives to Laboratory Animals (Journal of FRAME)
- DRG:
-
Dorsal Root Ganglion
- GFAP:
-
Glial Fibrillary Azidic Protein
- EC:
-
Endothelial Cell
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Atterwill, C. (1997). Current trends for the assessment of neurotoxicity in vitro. In: Schöffl, H., et al. Forschung ohne Tierversuche 1996. Ersatz- und Ergänzungsmethoden zu Tierversuchen. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6833-2_6
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