Abstract
Elevated levels of free bilirubin in the brain triggered by increased concentrations of unconjugated bilirubin (UCB) may cause adverse neurological outcomes. We aimed to evaluate: (i)the effects of UCB in neuronal apoptosis, oxidative stress and P-JNK1/2 expression; (ii) if UCB damages the neuritic tree and whether glycoursodeoxycholic acid (GUDCA), IL-10 or L-NAME are protective; (iii)the brain regional susceptibility to UCB-induced dendritic disruption.
Rat cortical neurons with 3 days in vitro (DIV) were incubated with 50 microM UCB plus 100 microM HSA. After 4h, we evaluated apoptosis (caspase-3 activity), P-JNK1/2 and nNOS expression (Western blot) and nitrites (Griess reagent). Following 24h, neurite arborization (MAP-2 labeling) was evaluated. Cells were also incubated with 50 microM GUDCA, 10 ng/mL IL-10 or 100 microM L-NAME prior to UCB exposure. Neurons from hippocampus and cerebellum at 3 DIV were also exposed to UCB (24h) to assess neuritic arborization.
UCB increased caspase-3 activity (1.5-fold, p< 0.01), P-JNK1/2 (1.3-fold, p< 0.01) and nNOS (1.2- fold, p< 0.01), as well as NO production (1.7-fold, p< 0.01). Moreover, UCB decreased neurite extension (0.8-fold, p< 0.05) and ramification (0.5-fold, p< 0.05), effects that were prevented by GUDCA (p< 0.05 vs UCB), IL-10 and L-NAME (extension, p< 0.05; ramification, p< 0.01 vs UCB). Hippocampus revealed the utmost reduction in neurite ramification (46%, p< 0.01) and extension (28%, p< 0.05).
Neuronal dysfunction by UCB comprises several intracellular pathways involving oxidative injury and disruption of neurite arborization. Anti-oxidant and/or anti-inflammatory compounds prevent UCB-damage to neuronal network. Hippocampus reveals the higher neurotoxicty by UCB. Funding:FCT- PTDC/SAU-NEU/64385/2006.
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Vaz, A., Silva, S., Falcão, A. et al. 246 Bilirubin in the Brain: Neurotoxic Effects, Therapeutic Promises and Regional Vulnerability. Pediatr Res 68 (Suppl 1), 128 (2010). https://doi.org/10.1203/00006450-201011001-00246
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DOI: https://doi.org/10.1203/00006450-201011001-00246
