Abstract
Objective
Jaundice (icterus) is the visible manifestation of the accumulation of bilirubin in the tissue and is indicative of potential toxicity to the brain. Since its very first description more than 2000 years ago, many efforts have been undertaken to understand the molecular determinants of bilirubin toxicity to neuronal cells to reduce the risk of neurological sequelae through the use of available chemicals and in vitro, ex vivo, in vivo, and clinical models. Although several studies have been performed, important questions remain unanswered, such as the reasons for regional sensitivity and the interplay with brain development. The number of new molecular effects identified has increased further, which has added even more complexity to the understanding of the condition. As new research challenges emerged, so does the need to establish solid models of prematurity.
Methods
This review critically summarizes the key mechanisms of severe neonatal hyperbilirubinemia and the use of the available models and technologies for translational research.
Impact
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We critically review the conceptual dogmas and models used for studying bilirubin-induced neurotoxicity.
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We point out the pitfalls and translational gaps, and suggest new clinical research challenges.
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We hope to inform researchers on the pro and cons of the models used, and to help direct their experimental focus in a most translational research.
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Data availability
All data generated or analyzed during this study are included in this published article.
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Acknowledgements
We sincerely thank Prof. Jon F. Watchko for his inspiring presentation at the “Yellow seminars” of December 6, 2021 (http://bit.ly/YW_Watchko), and Dr Lorraine Kay Cabral for critical reading of this review.
Funding
S.J., C.T., and S.G. were financed in part by an internal grant of the Fondazione Italiana Fegato – Onlus. S.J. was financed by a fellowship from the Lembaga Pengelola Dana Pendidikan (Indonesia Endowment Fund for Education), in part by an internal grant of the Fondazione Italiana Fegato – Onlus.
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S.G. made substantial contribution to conception and design, acquisition, and revision of the literature, and wrote the article. S.J. contributed to acquisition and revision of the literature and wrote the article. C.T. discussed the results, revised the article for intellectual content, and contributed to the final revision of the English. All the authors read and approved the final version of the article.
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Gazzin, S., Jayanti, S. & Tiribelli, C. Models of bilirubin neurological damage: lessons learned and new challenges. Pediatr Res 93, 1838–1845 (2023). https://doi.org/10.1038/s41390-022-02351-x
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DOI: https://doi.org/10.1038/s41390-022-02351-x
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