Bilirubin injury to neurons and glial cells: new players, novel targets, and newer insights.

Encephalopathy by hyperbilirubinemia in infants has been described for decades, but neither the underlying cellular and molecular mechanisms nor the selective pattern of bilirubin deposition in the brain is well understood. The brain is composed of highly specialized and diverse populations of cells, represented by neurons and glia that comprise astrocytes, oligodendrocytes, and microglia. Although microscopic evaluation of icteric brain sections revealed bilirubin within neurons, neuronal processes, and microglia, cell dependent-sensitivity to bilirubin toxicity and the role of each nerve cell type are poorly understood. Even less considered are glial and neuronal pathologic alterations as integrated phenomena. The available knowledge on reactivity of glial cells to bilirubin and on the impairment to neuronal network dynamics that it causes, here summarized, suggests that a better comprehension of the interplay between neurons and glia is essential to understand bilirubin neurotoxicity and highlight potential molecular targets that may lead to disease-modifying therapeutic approaches.