title: Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment.
abstract: The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity.
authors.affiliation: Italian Liver Foundation (Fondazione Italiana Fegato), AREA Science Park, Trieste, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Ben
authors.affiliation: Department of Medical Sciences (Dipartimento di Scienze Mediche), Ospedale di Cattinara, Univestità degli Studi di Trieste, Trieste, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottin
authors.affiliation: Department of Medical Sciences (Dipartimento di Scienze Mediche), Ospedale di Cattinara, Univestità degli Studi di Trieste, Trieste, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Zanconati
authors.affiliation: Italian Liver Foundation (Fondazione Italiana Fegato), AREA Science Park, Trieste, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiribelli
authors.affiliation: Italian Liver Foundation (Fondazione Italiana Fegato), AREA Science Park, Trieste, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gazzin
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D001928:Brain Diseases, Metabolic / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D004660:Encephalitis / Q000473:pathology*; D006932:Hyperbilirubinemia / Q000150:complications*; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D015636:Magnesium Chloride / Q000494:pharmacology; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D018384:Oxidative Stress; D051381:Rats
chemical_list: D018696:Neuroprotective Agents; D015636:Magnesium Chloride; D003474:Curcumin; D001663:Bilirubin; D007213:Indomethacin