Editorial [Hot Topic: Bilirubin Induced Neurological Damage: From the Cell to the Newborn (Executive Editor: J.D. Ostrow and C. Tiribelli)]

The principal aim of this special issue is to critically and translationally review the pathophysiology of bilirubin-induced neurological disease (BIND). Understanding the mechanisms of BIND can point the way to new diagnostic methods to predict the development of acute BIND and to prevent and treat it more effectively. Kernicterus is a rare disease of the nervous system, seen mostly in severely jaundiced neonates; its incidence is less than 1 in 30,000 jaundiced neonates (<1 per 50,000 neonates) [1]. Kernicterus is characterized by the deposition of the tetrapyrrolic bile pigment, unconjugated bilirubin (UCB) in the basal ganglia, hippocampus, and in several nuclear clusters of the brainstem and cerebellum. This results in a characteristic yellow staining of these brain nuclei, associated with impairment or loss of their function (encephalopathy) that is frequently irreversible. The molecular mechanisms by which UCB affects cellular functions have been elucidated only in the past two decades [2]. Recent major advances have clarified the relationships between the physicochemical structure and biological effects of UCB, which is an antioxidant and cytoprotective at low concentrations and cytotoxic at higher concentrations [3]. Therefore two chapters are devoted to an update of these important dual effects of UCB [4, 5]. Recent discoveries regarding the roles of ATP-binding cassette (ABC) proteins in maintaining low intracellular concentrations of the pigment have been followed by study of the strategic localization of these transporters in different regions of the CNS [2, 6, 7]. The critical role of the ABC proteins and their possible utilization as therapeutic targets are reviewed [8]. In vitro and in vivo studies have revealed the complicated network of sequential reactions that result in UCB cytotoxicity, offering multiple targets for potential therapeutic interventions [9, 10]. This includes also the passage of UCB across the two main barriers separating plasma and cerebrospinal fluid from neurons, astrocytes and glia. The role of these barriers is critically reviewed by Ghersi-Egea [11]. It is becoming increasingly clear that the unbound (free) fraction of plasma and tissue bilirubin (Bf) is the biologically active moiety that determines cytotoxicity [12, 13]. This concept is only just gaining recognition by those caring for jaundiced newborn infants, but additional clinical studies are needed to establish the true prognostic value of measurement of plasma Bf. This important point is reviewed [14,15]. This special issue is designed to rectify the lack of any recent, comprehensive, translational review of the mechanisms of BIND. It was assembled to update the advances of the past two decades and point the way to further investigations. We are grateful to all the authors for their thorough reviews of their individual areas of expertise.