{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:15:23Z","timestamp":1780550123116,"version":"3.54.1"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T00:00:00Z","timestamp":1484784000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T00:00:00Z","timestamp":1484784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>in vitro<\/jats:italic> the cellular complexity, connection and architecture of the <jats:italic>in vivo<\/jats:italic> 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\u201313 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, MgCl<jats:sub>2<\/jats:sub>) 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.<\/jats:p>","DOI":"10.1038\/srep41032","type":"journal-article","created":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T14:42:58Z","timestamp":1484836978000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment"],"prefix":"10.1038","volume":"7","author":[{"given":"Matteo","family":"Dal Ben","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bottin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Zanconati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Gazzin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,1,19]]},"reference":[{"key":"BFsrep41032_CR1","first-page":"1","volume":"129","author":"K-H Wagner","year":"2015","unstructured":"Wagner, K.-H. et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin. Sci. Lond. Engl. 1979 129, 1\u201325 (2015).","journal-title":"Clin. Sci. Lond. Engl. 1979"},{"key":"BFsrep41032_CR2","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/S0022-2275(20)39768-6","volume":"35","author":"JD Ostrow","year":"1994","unstructured":"Ostrow, J. D., Mukerjee, P. & Tiribelli, C. Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function. J. Lipid Res. 35, 1715\u20131737 (1994).","journal-title":"J. Lipid Res."},{"key":"BFsrep41032_CR3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1203\/01.PDR.0000067486.79854.D5","volume":"54","author":"JD Ostrow","year":"2003","unstructured":"Ostrow, J. D., Pascolo, L. & Tiribelli, C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro . Pediatr. Res. 54, 98\u2013104 (2003).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR4","doi-asserted-by":"crossref","unstructured":"American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 114, 297\u2013316 (2004).","DOI":"10.1542\/peds.114.1.297"},{"key":"BFsrep41032_CR5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1053\/j.semperi.2004.09.006","volume":"28","author":"VK Bhutani","year":"2004","unstructured":"Bhutani, V. K., Johnson, L. H. & Shapiro, S. M. Kernicterus in sick and preterm infants (1999\u20132002): a need for an effective preventive approach. Semin. Perinatol. 28, 319\u2013325 (2004).","journal-title":"Semin. Perinatol."},{"key":"BFsrep41032_CR6","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/pr.2013.208","volume":"74","author":"VK Bhutani","year":"2013","unstructured":"Bhutani, V. K. et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr. Res. 74 Suppl 1, 86\u2013100 (2013).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR7","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1056\/NEJMra1308124","volume":"369","author":"JF Watchko","year":"2013","unstructured":"Watchko, J. F. & Tiribelli, C. Bilirubin-induced neurologic damage\u2013mechanisms and management approaches. N. Engl. J. Med. 369, 2021\u20132030 (2013).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep41032_CR8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.siny.2009.12.004","volume":"15","author":"SM Shapiro","year":"2010","unstructured":"Shapiro, S. M. Chronic bilirubin encephalopathy: diagnosis and outcome. Semin. Fetal. Neonatal Med. 15, 157\u2013163 (2010).","journal-title":"Semin. Fetal. Neonatal Med."},{"key":"BFsrep41032_CR9","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1373\/clinchem.2008.121269","volume":"55","author":"CE Ahlfors","year":"2009","unstructured":"Ahlfors, C. E., Wennberg, R. P., Ostrow, J. D. & Tiribelli, C. Unbound (free) bilirubin: improving the paradigm for evaluating neonatal jaundice. Clin. Chem. 55, 1288\u20131299 (2009).","journal-title":"Clin. Chem."},{"key":"BFsrep41032_CR10","first-page":"511","volume":"108","author":"D Rice","year":"2000","unstructured":"Rice, D. & Barone, S. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ. Health Perspect. 108 Suppl 3, 511\u2013533 (2000).","journal-title":"Environ. Health Perspect."},{"key":"BFsrep41032_CR11","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0165-0270(91)90128-M","volume":"37","author":"L Stoppini","year":"1991","unstructured":"Stoppini, L., Buchs, P. A. & Muller, D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173\u2013182 (1991).","journal-title":"J. Neurosci. Methods"},{"key":"BFsrep41032_CR12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0166-2236(97)01122-3","volume":"20","author":"BH G\u00e4hwiler","year":"1997","unstructured":"G\u00e4hwiler, B. H., Capogna, M., Debanne, D., McKinney, R. A. & Thompson, S. M. Organotypic slice cultures: a technique has come of age. Trends Neurosci. 20, 471\u2013477 (1997).","journal-title":"Trends Neurosci"},{"key":"BFsrep41032_CR13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.pneurobio.2009.01.002","volume":"88","author":"L Lossi","year":"2009","unstructured":"Lossi, L., Alasia, S., Salio, C. & Merighi, A. Cell death and proliferation in acute slices and organotypic cultures of mammalian CNS. Prog. Neurobiol. 88, 221\u2013245 (2009).","journal-title":"Prog. Neurobiol."},{"key":"BFsrep41032_CR14","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/s00431-005-0055-2","volume":"165","author":"KA Strauss","year":"2006","unstructured":"Strauss, K. A. et al. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease. Eur. J. Pediatr. 165, 306\u2013319 (2006).","journal-title":"Eur. J. Pediatr."},{"key":"BFsrep41032_CR15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1159\/000103740","volume":"92","author":"AS Geiger","year":"2007","unstructured":"Geiger, A. S., Rice, A. C. & Shapiro, S. M. Minocycline blocks acute bilirubin-induced neurological dysfunction in jaundiced Gunn rats. Neonatology 92, 219\u2013226 (2007).","journal-title":"Neonatology"},{"key":"BFsrep41032_CR16","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/j.1460-9568.2005.04182.x","volume":"22","author":"S Lin","year":"2005","unstructured":"Lin, S. et al. Minocycline blocks bilirubin neurotoxicity and prevents hyperbilirubinemia-induced cerebellar hypoplasia in the Gunn rat. Eur. J. Neurosci. 22, 21\u201327 (2005).","journal-title":"Eur. J. Neurosci"},{"key":"BFsrep41032_CR17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/oxfordjournals.jhered.a104478","volume":"29","author":"CH Gunn","year":"1938","unstructured":"Gunn, C. H. Hereditary Acholuric Jaundice in a New Mutant Strain of Rats. J. Hered. 29, 137\u2013139 (1938).","journal-title":"J. Hered."},{"key":"BFsrep41032_CR18","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S1043-6618(02)00123-8","volume":"46","author":"AI Ghoneim","year":"2002","unstructured":"Ghoneim, A. I., Abdel-Naim, A. B., Khalifa, A. E. & El-Denshary, E. S. Protective effects of curcumin against ischaemia\/reperfusion insult in rat forebrain. Pharmacol. Res. 46, 273\u2013279 (2002).","journal-title":"Pharmacol. Res."},{"key":"BFsrep41032_CR19","doi-asserted-by":"crossref","first-page":"8370","DOI":"10.1523\/JNEUROSCI.21-21-08370.2001","volume":"21","author":"GP Lim","year":"2001","unstructured":"Lim, G. P. et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci. Off. J. Soc. Neurosci. 21, 8370\u20138377 (2001).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep41032_CR20","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1001\/jama.290.20.2669","volume":"290","author":"CA Crowther","year":"2003","unstructured":"Crowther, C. A., Hiller, J. E., Doyle, L. W. & Haslam, R. R. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 290, 2669\u20132676 (2003).","journal-title":"JAMA"},{"key":"BFsrep41032_CR21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/2040-7378-5-6","volume":"5","author":"T Westermaier","year":"2013","unstructured":"Westermaier, T. et al. Magnesium treatment for neuroprotection in ischemic diseases of the brain. Exp. Transl. Stroke Med. 5, 6 (2013).","journal-title":"Exp. Transl. Stroke Med"},{"key":"BFsrep41032_CR22","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.nbd.2006.02.015","volume":"23","author":"O Chechneva","year":"2006","unstructured":"Chechneva, O., Dinkel, K., Cavaliere, F., Martinez-Sanchez, M. & Reymann, K. G. Anti-inflammatory treatment in oxygen-glucose-deprived hippocampal slice cultures is neuroprotective and associated with reduced cell proliferation and intact neurogenesis. Neurobiol. Dis. 23, 247\u2013259 (2006).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep41032_CR23","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1542\/peds.2005-1767","volume":"117","author":"SP Miller","year":"2006","unstructured":"Miller, S. P. et al. Prolonged indomethacin exposure is associated with decreased white matter injury detected with magnetic resonance imaging in premature newborns at 24 to 28 weeks\u2019 gestation at birth. Pediatrics 117, 1626\u20131631 (2006).","journal-title":"Pediatrics"},{"key":"BFsrep41032_CR24","first-page":"513","volume":"35","author":"VK Agrawal","year":"1998","unstructured":"Agrawal, V. K., Shukla, R., Misra, P. K., Kapoor, R. K. & Malik, G. K. Brainstem auditory evoked response in newborns with hyperbilirubinemia. Indian Pediatr. 35, 513\u2013518 (1998).","journal-title":"Indian Pediatr."},{"key":"BFsrep41032_CR25","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/BF02758564","volume":"73","author":"P Sharma","year":"2006","unstructured":"Sharma, P. et al. Brainstem evoked response audiometry (BAER) in neonates with hyperbilirubinemia. Indian J. Pediatr. 73, 413\u2013416 (2006).","journal-title":"Indian J. Pediatr."},{"key":"BFsrep41032_CR26","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1203\/00006450-198802000-00018","volume":"23","author":"TW Hansen","year":"1988","unstructured":"Hansen, T. W., Bratlid, D. & Walaas, S. I. Bilirubin decreases phosphorylation of synapsin I, a synaptic vesicle-associated neuronal phosphoprotein, in intact synaptosomes from rat cerebral cortex. Pediatr. Res. 23, 219\u2013223 (1988).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR27","doi-asserted-by":"crossref","first-page":"e96171","DOI":"10.1371\/journal.pone.0096171","volume":"9","author":"S Song","year":"2014","unstructured":"Song, S., Hu, Y., Gu, X., Si, F. & Hua, Z. A novel newborn rat kernicterus model created by injecting a bilirubin solution into the cisterna magna. PloS One 9, e96171 (2014).","journal-title":"PloS One"},{"key":"BFsrep41032_CR28","first-page":"54","volume":"25","author":"SM Shapiro","year":"2005","unstructured":"Shapiro, S. M. Definition of the clinical spectrum of kernicterus and bilirubin-induced neurologic dysfunction (BIND). J. Perinatol. Off. J. Calif. Perinat. Assoc. 25, 54\u201359 (2005).","journal-title":"J. Perinatol. Off. J. Calif. Perinat. Assoc"},{"key":"BFsrep41032_CR29","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1203\/00006450-200207000-00023","volume":"52","author":"D G\u00fcrses","year":"2002","unstructured":"G\u00fcrses, D., Kili\u00e7, I. & Sahiner, T. Effects of hyperbilirubinemia on cerebrocortical electrical activity in newborns. Pediatr. Res. 52, 125\u2013130 (2002).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR30","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.jpeds.2008.10.049","volume":"154","author":"S Zangen","year":"2009","unstructured":"Zangen, S. et al. Fatal kernicterus in a girl deficient in glucose-6-phosphate dehydrogenase: a paradigm of synergistic heterozygosity. J. Pediatr. 154, 616\u2013619 (2009).","journal-title":"J. Pediatr."},{"key":"BFsrep41032_CR31","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.nbd.2005.03.001","volume":"20","author":"AS Falc\u00e3o","year":"2005","unstructured":"Falc\u00e3o, A. S., Fernandes, A., Brito, M. A., Silva, R. F. M. & Brites, D. Bilirubin-induced inflammatory response, glutamate release, and cell death in rat cortical astrocytes are enhanced in younger cells. Neurobiol. Dis. 20, 199\u2013206 (2005).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep41032_CR32","doi-asserted-by":"crossref","unstructured":"Gambaro, S. E., Robert, M. C., Tiribelli, C. & Gazzin, S. Role of brain cytochrome P450 mono-oxygenases in bilirubin oxidation-specific induction and activity. Arch. Toxicol., doi: 10.1007\/s00204-014-1394-4 (2014).","DOI":"10.1007\/s00204-014-1394-4"},{"key":"BFsrep41032_CR33","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13041-014-0087-5","volume":"7","author":"W Hu","year":"2014","unstructured":"Hu, W. et al. Ex vivo (1)H nuclear magnetic resonance spectroscopy reveals systematic alterations in cerebral metabolites as the key pathogenetic mechanism of bilirubin encephalopathy. Mol. Brain 7, 87 (2014).","journal-title":"Mol. Brain"},{"key":"BFsrep41032_CR34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0168-0102(89)90060-6","volume":"6","author":"H Keino","year":"1989","unstructured":"Keino, H. & Kashiwamata, S. Critical period of bilirubin-induced cerebellar hypoplasia in a new Sprague-Dawley strain of jaundiced Gunn rats. Neurosci. Res. 6, 209\u2013215 (1989).","journal-title":"Neurosci. Res."},{"key":"BFsrep41032_CR35","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1111\/j.1442-200X.2009.02878.x","volume":"51","author":"Y-K Lee","year":"2009","unstructured":"Lee, Y.-K., Daito, Y., Katayama, Y., Minami, H. & Negishi, H. The significance of measurement of serum unbound bilirubin concentrations in high-risk infants. Pediatr. Int. Off. J. Jpn. Pediatr. Soc. 51, 795\u2013799 (2009).","journal-title":"Pediatr. Int. Off. J. Jpn. Pediatr. Soc"},{"key":"BFsrep41032_CR36","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1007\/s004010050639","volume":"93","author":"JW Conlee","year":"1997","unstructured":"Conlee, J. W. & Shapiro, S. M. Development of cerebellar hypoplasia in jaundiced Gunn rats: a quantitative light microscopic analysis. Acta Neuropathol. (Berl.) 93, 450\u2013460 (1997).","journal-title":"Acta Neuropathol. (Berl.)"},{"key":"BFsrep41032_CR37","doi-asserted-by":"crossref","first-page":"14108","DOI":"10.1073\/pnas.0804650106","volume":"106","author":"F Bandeira","year":"2009","unstructured":"Bandeira, F., Lent, R. & Herculano-Houzel, S. Changing numbers of neuronal and non-neuronal cells underlie postnatal brain growth in the rat. Proc. Natl. Acad. Sci. USA 106, 14108\u201314113 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep41032_CR38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/toxsci\/68.1.9","volume":"68","author":"KA Haberny","year":"2002","unstructured":"Haberny, K. A. et al. Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol. Sci. Off. J. Soc. Toxicol. 68, 9\u201317 (2002).","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol"},{"key":"BFsrep41032_CR39","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1523\/JNEUROSCI.1901-08.2008","volume":"28","author":"MA Galic","year":"2008","unstructured":"Galic, M. A. et al. Postnatal inflammation increases seizure susceptibility in adult rats. J. Neurosci. Off. J. Soc. Neurosci. 28, 6904\u20136913 (2008).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"BFsrep41032_CR40","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1007\/s12035-013-8530-7","volume":"49","author":"A Barateiro","year":"2014","unstructured":"Barateiro, A., Domingues, H. S., Fernandes, A., Relvas, J. B. & Brites, D. Rat cerebellar slice cultures exposed to bilirubin evidence reactive gliosis, excitotoxicity and impaired myelinogenesis that is prevented by AMPA and TNF-\u03b1 inhibitors. Mol. Neurobiol. 49, 424\u2013439 (2014).","journal-title":"Mol. Neurobiol."},{"key":"BFsrep41032_CR41","first-page":"1052","volume":"26","author":"G Bortolussi","year":"2012","unstructured":"Bortolussi, G. et al. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 26, 1052\u20131063 (2012).","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol"},{"key":"BFsrep41032_CR42","first-page":"1057","volume":"7","author":"G Bortolussi","year":"2014","unstructured":"Bortolussi, G. et al. Age-dependent pattern of cerebellar susceptibility to bilirubin neurotoxicity in vivo in mice. Dis. Model. Mech. 7, 1057\u20131068 (2014).","journal-title":"Dis. Model. Mech"},{"key":"BFsrep41032_CR43","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/pr.2012.23","volume":"71","author":"S Gazzin","year":"2012","unstructured":"Gazzin, S. et al. Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups. Pediatr. Res. 71, 653\u2013660 (2012).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR44","doi-asserted-by":"crossref","first-page":"e79073","DOI":"10.1371\/journal.pone.0079073","volume":"8","author":"MC Robert","year":"2013","unstructured":"Robert, M. C. et al. Alterations in the cell cycle in the cerebellum of hyperbilirubinemic Gunn rat: a possible link with apoptosis? PloS One 8, e79073 (2013).","journal-title":"PloS One"},{"key":"BFsrep41032_CR45","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1177\/0883073811423975","volume":"27","author":"MA Brito","year":"2012","unstructured":"Brito, M. A. et al. Cerebellar axon\/myelin loss, angiogenic sprouting, and neuronal increase of vascular endothelial growth factor in a preterm infant with kernicterus. J. Child Neurol. 27, 615\u2013624 (2012).","journal-title":"J. Child Neurol."},{"key":"BFsrep41032_CR46","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S0887-8994(02)00425-3","volume":"27","author":"B Tabarki","year":"2002","unstructured":"Tabarki, B., Khalifa, M., Yacoub, M., Tlili, K. & Essoussi, A. S. Cerebellar symptoms heralding bilirubin encephalopathy in Crigler-Najjar syndrome. Pediatr. Neurol. 27, 234\u2013236 (2002).","journal-title":"Pediatr. Neurol."},{"key":"BFsrep41032_CR47","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1016\/j.neuropharm.2012.02.002","volume":"62","author":"SL Silva","year":"2012","unstructured":"Silva, S. L. et al. Neuritic growth impairment and cell death by unconjugated bilirubin is mediated by NO and glutamate, modulated by microglia, and prevented by glycoursodeoxycholic acid and interleukin-10. Neuropharmacology 62, 2398\u20132408 (2012).","journal-title":"Neuropharmacology"},{"key":"BFsrep41032_CR48","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/pr.2012.111","volume":"72","author":"MJ Daood","year":"2012","unstructured":"Daood, M. J., Hoyson, M. & Watchko, J. F. Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups. Pediatr. Res. 72, 455\u2013459 (2012).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR49","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1203\/01.pdr.0000219561.07550.04","volume":"60","author":"MJ Daood","year":"2006","unstructured":"Daood, M. J. & Watchko, J. F. Calculated in vivo free bilirubin levels in the central nervous system of Gunn rat pups. Pediatr. Res. 60, 44\u201349 (2006).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR50","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1203\/01.pdr.0000245992.89965.94","volume":"60","author":"L Roca","year":"2006","unstructured":"Roca, L. et al. Factors affecting the binding of bilirubin to serum albumins: validation and application of the peroxidase method. Pediatr. Res. 60, 724\u2013728 (2006).","journal-title":"Pediatr. Res."},{"key":"BFsrep41032_CR51","doi-asserted-by":"crossref","first-page":"e29078","DOI":"10.1371\/journal.pone.0029078","volume":"6","author":"PJ Giraudi","year":"2011","unstructured":"Giraudi, P. J., Bellarosa, C., Coda-Zabetta, C. D., Peruzzo, P. & Tiribelli, C. Functional induction of the cystine-glutamate exchanger system Xc(-) activity in SH-SY5Y cells by unconjugated bilirubin. PloS One 6, e29078 (2011).","journal-title":"PloS One"},{"key":"BFsrep41032_CR52","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s00401-006-0078-4","volume":"112","author":"AS Falc\u00e3o","year":"2006","unstructured":"Falc\u00e3o, A. S., Fernandes, A., Brito, M. A., Silva, R. F. M. & Brites, D. Bilirubin-induced immunostimulant effects and toxicity vary with neural cell type and maturation state. Acta Neuropathol. (Berl.) 112, 95\u2013105 (2006).","journal-title":"Acta Neuropathol. (Berl.)"},{"key":"BFsrep41032_CR53","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1111\/j.1471-4159.2006.03680.x","volume":"96","author":"A Fernandes","year":"2006","unstructured":"Fernandes, A. et al. Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin. J. Neurochem. 96, 1667\u20131679 (2006).","journal-title":"J. Neurochem."},{"key":"BFsrep41032_CR54","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/1742-2094-9-56","volume":"9","author":"K Liaury","year":"2012","unstructured":"Liaury, K. et al. Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model. J. Neuroinflammation 9, 56 (2012).","journal-title":"J. Neuroinflammation"},{"key":"BFsrep41032_CR55","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cellsig.2013.11.029","volume":"26","author":"M Qaisiya","year":"2014","unstructured":"Qaisiya, M., Coda Zabetta, C. D., Bellarosa, C. & Tiribelli, C. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell. Signal. 26, 512\u2013520 (2014).","journal-title":"Cell. Signal."},{"key":"BFsrep41032_CR56","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.nbd.2010.08.010","volume":"40","author":"SL Silva","year":"2010","unstructured":"Silva, S. L. et al. Features of bilirubin-induced reactive microglia: from phagocytosis to inflammation. Neurobiol. Dis. 40, 663\u2013675 (2010).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep41032_CR57","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","volume":"55","author":"SA Bustin","year":"2009","unstructured":"Bustin, S. A. et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 55, 611\u2013622 (2009).","journal-title":"Clin. Chem."},{"key":"BFsrep41032_CR58","unstructured":"Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002)."},{"key":"BFsrep41032_CR59","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1006\/exnr.2000.7518","volume":"166","author":"S Grojean","year":"2000","unstructured":"Grojean, S., Koziel, V., Vert, P. & Daval, J. L. Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons. Exp. Neurol. 166, 334\u2013341 (2000).","journal-title":"Exp. Neurol."},{"key":"BFsrep41032_CR60","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1006\/exnr.1997.6762","volume":"150","author":"JW McDonald","year":"1998","unstructured":"McDonald, J. W., Shapiro, S. M., Silverstein, F. S. & Johnston, M. V. Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model. Exp. Neurol. 150, 21\u201329 (1998).","journal-title":"Exp. Neurol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep41032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41032","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep41032.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T00:32:31Z","timestamp":1671841951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep41032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,1,19]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,2,20]]}},"alternative-id":["BFsrep41032"],"URL":"https:\/\/doi.org\/10.1038\/srep41032","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,1,19]]},"assertion":[{"value":"11 October 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 February 2017","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The version of this Article previously published quoted an incorrect abbreviation for Matteo Dal Ben in the 'How to cite this article' section. This has now been corrected in the PDF and HTML versions of the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41032"}}