Biological risks for neurological abnormalities associated with hyperbilirubinemia

Abstract

Unconjugated bilirubin (UCB) injury to glial cells leads to the secretion of glutamate and elicits a typical inflammatory response. Release of pro-inflammatory cytokines may influence gliogenesis and neurogenesis, and lead to deficits in learning and memory. Glutamate metabolism dysregulation and overexpression of tumor necrosis factor-a (TNF-a) and interleukin (IL)-1b are consistent with schizophrenia neuropathology. Recently, an increased prevalence of schizophrenia was reported in individuals with Gilbert's syndrome and among those who have had elevated levels of UCB in the neonatal life. In this review, we explore the reactivity of astrocytes, neurons and microglia to UCB, the cascade of events implicated in the immunostimulant effects of UCB, as well as the role of each nerve cell type and maturation state in the neuropathology of UCB. Identification of the signaling events promoted by UCB will be relevant for developing novel therapies that might reduce the risk of brain injury and disabilities.

Bilirubin-induced neural impairment: A special focus on myelination, age-related windows of susceptibility and associated co-morbidities

“…Our in-vitro studies showed that bilirubin cytotoxicity is enhanced in undifferentiated astrocytes and neurons as compared with more mature cells [20]. Recently, a study using a mouse model with a null mutation in the Ugt1 gene, which results in early neonatal lethality due to hyperbilirubinemia, has demonstrated that bilirubin exposure during each of the first three weeks of life results in different sequelae and that phototherapy was effective in the prevention of brain damage [17].…”

Astrocyte reactivity to unconjugated bilirubin requires TNF‐α and IL‐1β receptor signaling pathways

“…UCB elicits nerve cell injury through interaction with cellular membranes (Rodrigues et al, 2002a), by triggering oxidative and nitrosative stress (Brito et al 2008a,b), and accumulation of extracellular glutamate Fernandes et al, 2004;Gordo et al, 2006;Silva et al, 1999), producing a widespread of structural and functional alterations that culminate in cell death Rodrigues et al, 2002b;Silva et al, 2002). We have shown that UCB elicits the release of pro-inflammatory cytokines, such as TNF-a and IL-1b, by neurons , astrocytes (Fernandes et al, 2004, and microglia , through the activation of MAPK (i.e., p38, JNK1/2 and ERK1/2) and NF-jB signaling pathways at the intracellular level (Brites et al, 2009;Fernandes et al, 2006Fernandes et al, , 2007a. Interestingly, infection is considered a risk factor for the development of UCB encephalopathy (Dawodu et al, 1984), and septic or infected infants are treated for neonatal hyperbilirubinemia at lower levels of serum UCB (Hansen, 2001).…”

Bilirubin-Induced Audiologic Injury in Preterm Infants

“…[15,16] Exposure of neurons to bilirubin results in increased oxidative stress and decreased neuronal proliferation[17,18] and presynaptic neurodegeneration at central glutaminergic synapses. [19] Furthermore, bilirubin administration results in smaller spiral ganglion cell bodies, with decreased cellular density and selective loss of large cranial nerve VIII myelinated fibers.…”

“…[20,21] When exposed to bilirubin, neuronal supporting cells have been found to secrete inflammatory markers which contribute to increased blood-brain barrier permeability and bilirubin loading. [15,16]…”