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Molecular events in brain bilirubin toxicity revisited

Pediatric Research (2024)Cite this article

Abstract

The mechanisms involved in bilirubin neurotoxicity are still far from being fully elucidated. Several different events concur to damage mainly the neurons among which inflammation and alteration of the redox state play a major role. An imbalance of cellular calcium homeostasis has been recently described to be associated with toxic concentrations of bilirubin, and this disequilibrium may in turn elicit an inflammatory reaction. The different and age-dependent sensitivity to bilirubin damage must also be considered in describing the dramatic clinical picture of bilirubin-induced neurological damage (BIND) formerly known as kernicterus spectrum disorder (KSD). This review aims to critically address what is known and what is not in the molecular events of bilirubin neurotoxicity to provide hints for a better diagnosis and more successful treatments. Part of these concepts have been presented at the 38th Annual Audrey K. Brown Kernicterus Symposium of Pediatric American Society, Washington DC, May 1, 2023.

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Fig. 1: Prosurvival mechanisms activated by neurons to counteract bilirubin induced OS.
Fig. 2: Bilirubin causes ER-stress as an early event that provokes iCa2+ increase and activation of the cytosolic pathway that leads to apoptosis.
Fig. 3: Pro-inflammatory effects of bilirubin.
Fig. 4: Bilirubin mediated glutamate-neurotoxicity.

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Acknowledgements

This paper is dedicated to all the colleagues involved at various levels with the challenging though difficult research in bilirubin. Supported by an intramural research grant from Italian Liver Foundation (FIF).

Funding

S.G., C.B., and C.T., were financed in part by an internal grant of the Fondazione Italiana Fegato - Onlus. XX by

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  1. These authors contributed equally: Silvia Gazzin, Cristina Bellarosa.

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  1. Liver-Brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149, Trieste, Italy

    Silvia Gazzin, Cristina Bellarosa & Claudio Tiribelli

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Gazzin, S., Bellarosa, C. & Tiribelli, C. Molecular events in brain bilirubin toxicity revisited. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03084-9

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