Aging Confers Different Sensitivity to the Neurotoxic Properties of Unconjugated Bilirubin

Bilirubin: An Endogenous Product of Heme Degradation with Both Cytotoxic and Cytoprotective Properties: Fig. 1

“…Rodrigues et al (2002d) reported that the apoptotic effect of UCB in primary cultures of rat neurons and astrocytes decreases as a function of age-in-culture of these cells, thus confirming the earlier findings of Amit and Brenner (1993) in primary cultures of fetal rat glial cells. In contrast, the UCBinduced mitochondrial membrane permeabilization and cytochrome c release were 2-fold greater for mitochondria derived from older rats compared with younger rats (Rodrigues et al, 2002d). These authors concluded that the young rats are relatively resistant to UCB toxicity.…”

“…Ursodeoxycholic acid, a mitochondrial membrane-stabilizing agent that prevents the changes in mitochondrial transmembrane potential, almost completely abolished the UCB-induced membrane perturbation in isolated mitochondria (Rodrigues et al, 2002b) and inhibited the UCB-mediated apoptosis of neurons and astrocytes (Silva et al, 2001). Rodrigues et al (2002d) reported that the apoptotic effect of UCB in primary cultures of rat neurons and astrocytes decreases as a function of age-in-culture of these cells, thus confirming the earlier findings of Amit and Brenner (1993) in primary cultures of fetal rat glial cells. In contrast, the UCBinduced mitochondrial membrane permeabilization and cytochrome c release were 2-fold greater for mitochondria derived from older rats compared with younger rats (Rodrigues et al, 2002d).…”

Biological risks for neurological abnormalities associated with hyperbilirubinemia

“…In fact, we have shown that astrocytes cultured for 5 days in vitro (DIV), as well as 4 DIV neurons exposed to 86 mM UCB in the presence of 29 mM human serum albumin (HSA), reveal approximately twofold higher levels of apoptosis when compared with more differentiated astrocytes and neurons. 16 Our most recent studies using conditions that mimic a severe neonatal hyperbilirubinemia (UCB/HSA molar ratio of 1) corroborated the higher vulnerability of young nerve cells to UCB-induced apoptosis. 18,19 Astrocytes also presented an age dependence of lactate dehydrogenase release by UCB interaction, whereas neurons showed a much lower influence of cell differentiation.…”

“…13,14 In addition, there is a current opinion that immaturity is associated with a greater sensitivity to neuronal sequelae by UCB and that cell viability was shown to be directly related to aging-in-culture. 15 Studies performed by us 16 and others 17 in nerve cell culture models point out that UCB induces greater apoptosis in more immature cells when compared with older ones. In fact, we have shown that astrocytes cultured for 5 days in vitro (DIV), as well as 4 DIV neurons exposed to 86 mM UCB in the presence of 29 mM human serum albumin (HSA), reveal approximately twofold higher levels of apoptosis when compared with more differentiated astrocytes and neurons.…”

Hyperbilirubinemia and Bilirubin Toxicity in the Late Preterm Infant

“…Similarly, virtually nothing is known about potential developmental differences in human neuronal vulnerability to unconjugated bilirubin (UCB) in vivo. It has, however, been shown repeatedly that UCB-induced toxicity in vitro in murine-derived CNS primary cell cultures is modulated by culture age (ie, younger presumably less mature neurons and astrocytes are more susceptible to bilirubin-induced apoptosis and necrosis than their older presumably more mature counterparts) [28][29][30][31]. Whether these findings are reflective of a clinically relevant in vivo phenomenon is unclear, but they collectively suggest that CNS cellular maturity may be a factor in modulating UCB-induced injury.…”