The Evolving Landscape of Neurotoxicity by Unconjugated Bilirubin: Role of Glial Cells and Inflammation

Dora Brites

doi:10.3389/fphar.2012.00088

Abstract

Unconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Although generally harmless, some neonates may develop very high levels of unconjugated bilirubin (UCB), which may surpass the protective mechanisms of the brain in preventing UCB accumulation. In this case, both short-term and long-term neurodevelopmental disabilities, such as acute and chronic UCB encephalopathy, known as kernicterus, or more subtle alterations defined as bilirubin-induced neurological dysfunction (BIND) may be produced. There is a tremendous variability in babies’ vulnerability toward UCB for reasons not yet explained, but preterm birth, sepsis, hypoxia, and hemolytic disease are comprised as risk factors. Therefore, UCB levels and neurological abnormalities are not strictly correlated. Even nowadays, the mechanisms of UCB neurotoxicity are still unclear, as are specific biomarkers, and little is known about lasting sequelae attributable to hyperbilirubinemia. On autopsy, UCB was shown to be within neurons, neuronal processes, and microglia, and to produce loss of neurons, demyelination, and gliosis. In isolated cell cultures, UCB was shown to impair neuronal arborization and to induce the release of pro-inflammatory cytokines from microglia and astrocytes. However, cell dependent sensitivity to UCB toxicity and the role of each nerve cell type remains not fully understood. This review provides a comprehensive insight into cell susceptibilities and molecular targets of UCB in neurons, astrocytes, and oligodendrocytes, and on phenotypic and functional responses of microglia to UCB. Interplay among glia elements and cross-talk with neurons, with a special emphasis in the UCB-induced immunostimulation, and the role of sepsis in BIND pathogenesis are highlighted. New and interesting data on the anti-inflammatory and antioxidant activities of different pharmacological agents are also presented, as novel and promising additional therapeutic approaches to BIND.

Highlights

Jaundice occurs during the first week of life in most infants due to elevated levels of unconjugated bilirubin (UCB) by increased breakdown of fetal erythrocytes, deficient human serum albumin (HSA) transport to the liver, and inefficient conjugation
Even considering the higher GSH levels and the elevated resistance to UCB-induced oxidative stress in astrocytes, as compared to neurons, depletion of GSH was still observed after incubation with Bf concentrations of 0.1 and 1 μM (Brito et al, 2008b). Because all these aspects may contribute to the degeneration of astrocytes in brain parenchyma, compromising neuronal survival, and functional recovery after bilirubin-induced neurological dysfunction (BIND), we propose that astrocytes should be considered one of the targets when searching for novel therapeutics for preventing neurological sequelae by UCB in conditions where the most used clinical approaches evidence to fail
CONCLUSION we have still a long way to envisage the complex and diverse reactivity of astrocytes and microglia to UCB, and their cross-talk with neurons in BIND conditions, in the present review we attempted to provide information on how individual cell response depends on the time of exposure to UCB, on the associated stimuli and on the presence of each type of neural cell

Summary

INTRODUCTION

Jaundice occurs during the first week of life in most infants due to elevated levels of unconjugated bilirubin (UCB) by increased breakdown of fetal erythrocytes, deficient human serum albumin (HSA) transport to the liver, and inefficient conjugation. Induction of necrotic-like cell death by UCB was higher in astrocytes than in neurons, in immature than in mature cells, and more elevated than its own apoptosis (Figures 3A,B) Both hypoxia and combined oxygen–glucose deprivation (OGD) followed by reoxygenation demonstrated to increase astrocyte susceptibility to UCB injury (Falcão et al, 2007b), accounting as risk factors of BIND. UCB determines a fast increase in the extracellular glutamate content (Fernandes et al, 2004), mainly in immature astrocytes (Figure 3C; Falcão et al, 2005) that appears to result from the inhibition of its uptake by UCB (Silva et al, 1999), more effective in these glial cells than in neurons LPS has previously shown to inhibit www.frontiersin.org

Bone marrow cell suspension Spleen cell suspension

Findings

CONCLUSION