Bilirubin neurotoxicity: a narrative review on long lasting, insidious, and dangerous effects
Dora Brites, Rui F. M. Silva
Abstract
Background and Objective: Elevated levels of UCB due to overproduction and/or defective clearance can severely impact the CNS leading to fatal encephalopathy or kernicterus spectrum disorders (KSD) associated with motor and auditory impairments. Still unknown is the preferential distribution of UCB in specific CNS regions and the long-lasting disabilities derived from severe neonatal hyperbilirubinemia. One of the aspects that remains uncertain is how unconjugated hyperbilirubinemia determines neural cell sequelae that may predispose to the development of neurodevelopmental, psychiatric, and neurodegenerative disorders. How UCB damages neurons and glial cells, and the injuries that can occur in more susceptible brain areas, thus potentially leading to permanent CNS dysfunction, is far from being clear. In this review, we summarize the neuropathological effects of unconjugated bilirubin (UCB) and its free species (Bf) with a focus on the dysregulation of the central nervous system (CNS) cell homeostasis and subsequent toxic paracrine signaling effects. Direct or indirect actions of glial cells on UCB-induced neurodegeneration are also critically reviewed. Methods: An exhaustive electronic search of the literature was performed with PubMed and Google Scholar on bilirubin neurotoxicity-related topics to identify relevant articles from 1947 to 2021. Languages other than English, German and French were excluded. Key Content and Findings: We specifically focused on the neurotoxic species of UCB and provided neuro- and gliocentric views in the context of neurodevelopmental alterations. Potential novel neuroprotective and regenerative strategies, including the use of extracellular vesicles (EVs) and their loading with medicines or microRNAs, were also addressed. Our perspectives on the future application of human advanced models and EVs to investigate UCB-induced neurotoxicity/KSD and subsequent pathological insults in early-life and lasting outcomes are outlined. Conclusions: We believe that this information could provide the next step for newborn screening using promising noninvasive biomarkers in the era of precision medicine to develop new and combinatorial therapeutic approaches at the forefront of translation.