Bilirubin as a determinant for altered neurogenesis, neuritogenesis, and synaptogenesis

Abstract

Elevated levels of serum unconjugated bilirubin (UCB) in the first weeks of life may lead to long-term neurologic impairment. We previously reported that an early exposure of developing neurons to UCB, in conditions mimicking moderate to severe neonatal jaundice, leads to neuritic atrophy and cell death. Here, we have further analyzed the effect of UCB on nerve cell differentiation and neuronal development, addressing how UCB may affect the viability of undifferentiated neural precursor cells and their fate decisions, as well as the development of hippocampal neurons in terms of dendritic and axonal elongation and branching, the axonal growth cone morphology, and the establishment of dendritic spines and synapses. Our results indicate that UCB reduces the viability of proliferating neural precursors, decreases neurogenesis without affecting astrogliogenesis, and increases cellular dysfunction in differentiating cells. In addition, an early exposure of neurons to UCB decreases the number of dendritic and axonal branches at 3 and 9 days in vitro (DIV), and a higher number of neurons showed a smaller growth cone area. UCB-treated neurons also reveal a decreased density of dendritic spines and synapses at 21 DIV. Such deleterious role of UCB in neuronal differentiation, development, and plasticity may compromise the performance of the brain in later life.

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

“…In particular, we have previously demonstrated that PCs showed a neurodegenerative phenotype as determined by FluoroJade positivity, TUNEL assay and Sholl analysis [17, 18]. These data strengthen the concept that immature neurons are more sensitive to insults compared to more differentiated ones [51] and that bilirubin affects survival of neuronal precursors by impairing their neurogenesis, arborization and synaptic connectivity [17, 52]. …”

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

“…Moreover, they observed that a compromised motor/co-ordination function occurred when implementation of phototherapy was delayed. Similar alterations in neuronal/axonal unit involving decreased number of dendritic and axonal branches, smaller growth cone area, and reduced dendritic spines and synapses, were previously observed in immature neurons exposed to UCB [21]. Interestingly, treatment with glycoursodeoxycholic acid has shown several neuroprotective properties and no noticeable secondary effect, and the anti-inflammatory interleukin (IL)-10 prevented such reduction in neuritic arborization by UCB [22].…”

Audiologic impairment associated with bilirubin-induced neurologic damage

“…Exposure of neurons to bilirubin results in increased oxidative stress and decreased neuronal proliferation [18,19] and presynaptic neurodegeneration at central glutaminergic synapses [20]. Furthermore, bilirubin administration results in smaller spiral ganglion cell bodies, with decreased cellular density and selective loss of large cranial nerve VIII myelinated fibers [21,22].…”