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• W2100804518 abstract "Claudio Tiribelli, Centro Studi Fegato and University of Trieste, Trieste, Italy. The incidence of bilirubin-induced neurological dysfunction (BIND) in jaundiced newborns is likely increasing because of the early hospital discharge of the infants and the lack of defined criteria for, and mandatory reporting of, the diagnosis of BIND [[1]Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 114 (2004) 297–316.Google Scholar]. On the other hand, there have been recent advances in understanding the molecular mechanisms by which unconjugated bilirubin (UCB) enters and damages central nervous system (CNS) cells [2Ostrow J.D. Pascolo L. Shapiro S.M. Tiribelli C. New concepts in bilirubin encephalopathy.Eur J Clin Invest. 2003; 33: 988-997Crossref PubMed Scopus (110) Google Scholar, 3Ostrow J.D. Pascolo L. Brites D. Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity.Trends Mol Med. 2004; 10: 65-70Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar], suggesting new approaches for the early diagnosis, prevention and treatment of BIND. We, therefore, under the scientific sponsorship of EASL, organized an interactive workshop of experts in the fields of bilirubin metabolism, transport and toxicity, CNS structure and function, and the clinical management of jaundiced newborns. The presentations at the EASL Single Topic Conference held in Trieste on 1 and 2 October, 2004, summarized in this report, review what is known about BIND and provide guidance for future research. David K. Stevenson, Stanford University, Stanford, CA, USA. The new American Academy of Pediatrics Clinical Practice Guideline for the ‘Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation’ [[1]Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 114 (2004) 297–316.Google Scholar] encourages use of the term ‘acute bilirubin encephalopathy’ to describe the acute manifestations of UCB toxicity seen in the first weeks after birth, and the term ‘kernicterus’ to describe the chronic, permanent clinical sequelae of UCB toxicity. Specific recommendations include: identification of hemolysis using corrected end-tidal carbon monoxide measurements [[4]Stevenson D.K. Fanaroff A.A. Maisels M.J. Young B.W. Wong R.J. Vreman H.J. et al.Prediction of hyperbilirubinemia in near-term and term infants.J Perinatol. 2001; 21: S63-S72Crossref PubMed Scopus (14) Google Scholar]; use of an hour-specific total serum bilirubin (TSB) nomogram [[5]Bhutani V.K. Johnson L. Sivieri E.M. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns.Pediatrics. 1999; 103: 6-14Crossref PubMed Scopus (555) Google Scholar]; improvement in the accuracy and precision of TSB measurements and correlation with transcutaneous bilirubin measurements [[6]Maisels M.J. Kring E. Transcutaneous bilirubinometry decreases the need for serum bilirubin measurements and saves money.Pediatrics. 1997; 99: 599-601Crossref PubMed Scopus (84) Google Scholar] in newborns with differing risk factors for hyperbilirubinemia; evaluation of the safety and efficacy of pharmacologic therapies, such as the competitive inhibition of heme oxygenase (HO) with metalloporphyrins [[7]Ostrow J.D. Therapeutic amelioration of jaundice.Hepatology. 1988; 8: 683-689Crossref PubMed Scopus (16) Google Scholar]; dissemination of the information in the Guideline; and monitoring Guideline compliance. The Guideline does not address infants <35 weeks gestation, in particular, very low birth weight infants, who may be especially vulnerable to hearing loss and poor neurodevelopmental outcome, even with peak TSB levels as low as 10 mg/dL (171 μmol/L) [[8]Oh W. Tyson J.E. Fanaroff A.A. Vohr B.R. Perritt R. Stoll B.J. et al.Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants.Pediatrics. 2003; 112: 773-779Crossref PubMed Scopus (99) Google Scholar]. Although neonatal jaundice is normally a benign condition, increased bilirubin production (e.g. hemolysis) or decreased bilirubin elimination (e.g. conjugation defects) may engender dangerously high TSB levels, causing acute bilirubin encephalopathy and/or kernicterus in some infants. African-American infants have a high incidence of hemolysis due to glucose-6-phosphate dehydrogenase deficiency and deserve special attention [[9]Herschel M. Ryan M. Gelbart T. Kaplan M. Hemolysis and hyperbilirubinemia in an African American neonate heterozygous for glucose-6-phosphate dehydrogenase deficiency.J Perinatol. 2002; 22: 577-579Crossref PubMed Scopus (24) Google Scholar]. Early recognition of these complications would be facilitated by development of a multifactorial index of risk for selection of neonates who need chemoprevention or phototherapy. Measurement of unbound (free) UCB in plasma (Bf), which is the key to bilirubin neurotoxicity, is fundamental to proper assessment of the risk of BIND in jaundiced neonates. J. Donald Ostrow, MD, University Washington School of Medicine, Seattle, WA, USA. Internal hydrogen bonding of the fully protonated UCB diacid creates a folded, biplanar structure with both hydrophobic and polar regions arrayed radially [[10]Ostrow J.D. Mukerjee P. Tiribelli C. Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function.J Lipid Res. 1994; 35: 1715-1737Abstract Full Text PDF PubMed Google Scholar]. This precludes stable insertion into membranes [[11]Zucker S.D. Gössling W. Bootle E.J. Sterritt C. Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching.J Lipid Res. 2001; 42: 1377-1388PubMed Google Scholar], limits aqueous solubility (70 nM) [[10]Ostrow J.D. Mukerjee P. Tiribelli C. Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function.J Lipid Res. 1994; 35: 1715-1737Abstract Full Text PDF PubMed Google Scholar] and retards ionization of the –COOH groups, so that pK'a values are 8.1 and 8.4 [[10]Ostrow J.D. Mukerjee P. Tiribelli C. Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function.J Lipid Res. 1994; 35: 1715-1737Abstract Full Text PDF PubMed Google Scholar]. At pH 7.4, over 80% of unbound UCB (Bf) is the toxic diacid species [[10]Ostrow J.D. Mukerjee P. Tiribelli C. Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function.J Lipid Res. 1994; 35: 1715-1737Abstract Full Text PDF PubMed Google Scholar], that readily diffuses across membranes [[12]Zucker S.D. Gössling W. Hoppin A.G. Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes.J Biol Chem. 1999; 274: 10852-10862Crossref PubMed Scopus (106) Google Scholar], including the blood–brain barrier [[13]Rodriguez Garay E.A. Scremin O.U. Transfer of bilirubin-14C between blood, cerebrospinal fluid, and brain tissue.Am J Physiol. 1971; 221: 1264-1270PubMed Google Scholar]. Binding to plasma albumin limits passage of UCB into the CNS [14Diamond I. Schmid R. Experimental bilirubin encephalopathy. The mode of entry of bilirubin-14C into the central nervous system.J Clin Invest. 1966; 45: 678-689Crossref PubMed Scopus (166) Google Scholar, 15Takahashi M. Sugiyama K. Shumiya S. Nagase S. Penetration of bilirubin into the brain of albumin-deficient and jaundiced rats (AJR) and Nagase analbuminemic rats.J Biochem (Tokyo). 1984; 96: 1705-1712Crossref PubMed Scopus (26) Google Scholar]. The affinity of human serum albumin (HSA) for UCB is much lower than thought previously and decreases markedly with increasing [HSA] and [Cl−] [16Ahlfors C.E. Measurement of plasma unbound unconjugated bilirubin.Anal Biochem. 2000; 279: 130-135Crossref PubMed Scopus (75) Google Scholar, 17Weisiger R.A. Ostrow J.D. Koehler R.K. Webster C.C. Mukerjee P. Pascolo L. et al.Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method.J Biol Chem. 2001; 276: 29953-29960Crossref PubMed Scopus (96) Google Scholar], the presence of competitive inhibitors, and probably acidosis. Applying the new affinity constants reveals that toxicity to CNS cells in vitro occurs only at Bf>70 nM [[18]Ostrow J.D. Pascolo L. Tiribelli C. Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro.Pediatr Res. 2003; 54: 98-104Crossref PubMed Scopus (59) Google Scholar], but that UCB is neuroprotective at lower Bf values [[19]Dore S. Snyder S.H. Neuroprotective action of bilirubin against oxidative stress in primary hippocampal cultures.Ann NY Acad Sci. 1999; 890: 167-172Crossref PubMed Scopus (68) Google Scholar]. Toxicity thus is associated with formation of small UCB aggregates above aqueous saturation, and short exposure to high Bf is not a valid model for the clinically relevant condition of prolonged exposure at lower Bf [[20]Ostrow J.D. Tiribelli C. Editorial: new concepts in bilirubin neurotoxicity and the need for studies at clinically relevant bilirubin concentrations.J Hepatology. 2001; 34: 467-470Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. Data are needed on the cerebrospinal fluid (CSF) and brain tissue concentrations of total and unbound UCB when toxicity occurs. Conjugated and unconjugated bilirubin and biliverdin are potent antioxidants [21Stocker R. Yamamoto Y. McDonagh A.F. Glazer A.N. Ames B.N. Bilirubin is an antioxidant of possible physiological importance.Science. 1987; 235: 1043-1046Crossref PubMed Scopus (2661) Google Scholar, 22Stocker R. Peterhans E. Antioxidant properties of conjugated bilirubin and biliverdin: biologically relevant scavenging of hypochlorous acid.Free Radic Res Commun. 1989; 6: 57-66Crossref PubMed Scopus (86) Google Scholar], even when bound to HSA [[23]Stocker R. Glazer A.N. Ames B.N. Antioxidant activity of albumin-bound bilirubin.Proc Natl Acad Sci USA. 1987; 84: 5918-5922Crossref PubMed Scopus (620) Google Scholar]. They act by being themselves oxidized, consuming reactive oxygen species (ROS). The ability of very low [UCB] to protect cells against vastly higher concentrations of ROS is due to rapid enzymatic regeneration of UCB from biliverdin [[24]Barañano D.E. Rao M. Ferris C.D. Snyder S.H. From the cover: biliverdin reductase: a major physiologic cytoprotectant.Proc Natl Acad Sci USA. 2002; 99: 16093-16098Crossref PubMed Scopus (811) Google Scholar], new formation of UCB by heme oxygenase [[25]Greenberg D.A. The jaundice of the cell.Proc Natl Acad Sci USA. 2002; 99: 15837-15839Crossref PubMed Scopus (25) Google Scholar], and uptake of UCB dissociating from the very large reservoir of UCB bound to HSA in plasma. Stephen D. Zucker, University of Cincinnati, Cincinnati, OH, USA. It remains unknown which, if any, transporter is responsible for the uptake of UCB by the hepatocyte [26Briz O. Serrano M.A. Macias R.I. Gonzalez-Gallego J. Marin J.J.G. Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin.Biochem J. 2003; 371: 897-905Crossref PubMed Scopus (137) Google Scholar, 27Wang P. Kim R.B. Roy Chowdhury J. Wolkoff A.W. The human organic anion transport protein SLC21A6 is not sufficient for bilirubin transport.J Biol Chem. 2003; 278: 20695-20699Crossref PubMed Scopus (73) Google Scholar]. The diffuse yellow staining of many tissues in jaundiced neonates suggests that the entry of UCB into non-hepatic tissues occurs via passive diffusion. The physicochemical characteristics of the amphiphilic UCB molecule facilitate its interaction with the surface of phospholipid bilayers [[11]Zucker S.D. Gössling W. Bootle E.J. Sterritt C. Localization of bilirubin in phospholipid bilayers by parallax analysis of fluorescence quenching.J Lipid Res. 2001; 42: 1377-1388PubMed Google Scholar] and there is minimal steric constraint to passive diffusion of UCB through cellular membranes [[28]Hayward D. Schiff D. Fedunec S. Chan G. Davis P.J. Poznansky M.J. Bilirubin diffusion through lipid membranes.Biochim Biophys Acta. 1986; 860: 149-153Crossref PubMed Scopus (27) Google Scholar]. Stopped-flow fluorescence techniques show that UCB, but not conjugated bilirubin, rapidly diffuses through model membranes and rat hepatocyte membranes, with a first-order rate constant of 5.3 s−1 (t1/2 130 ms) [[12]Zucker S.D. Gössling W. Hoppin A.G. Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes.J Biol Chem. 1999; 274: 10852-10862Crossref PubMed Scopus (106) Google Scholar]. As confirmed by data presented by Richard A. Wennberg (University of Washington, Seattle, WA, USA), the uncharged UCB diacid diffuses rapidly and spontaneously across the bilayer of phospholipid vesicles, subsequently releasing its protons and acidifying the internal milieu of the vesicles [[12]Zucker S.D. Gössling W. Hoppin A.G. Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers and native hepatocyte membranes.J Biol Chem. 1999; 274: 10852-10862Crossref PubMed Scopus (106) Google Scholar]. Cellular uptake by simple diffusion can exhibit saturation kinetics, depending on the rate-limiting step [[29]Zucker S.D. Gössling W. Mechanism of hepatocellular uptake of albumin-bound bilirubin.Biochim Biophys Acta. 2000; 1463: 197-208Crossref PubMed Scopus (31) Google Scholar]. Hepatocellular uptake of UCB is more rapid for UCB bound to HSA than to BSA (bovine serum albumin), despite a threefold higher binding affinity of HSA for UCB. This is consistent with 9× higher solvation (off) rates from HSA than from BSA and indicates dissociation-limited diffusion, in which the rates of UCB transfer are determined mainly by the relative concentrations of donor and acceptor molecules [15Takahashi M. Sugiyama K. Shumiya S. Nagase S. Penetration of bilirubin into the brain of albumin-deficient and jaundiced rats (AJR) and Nagase analbuminemic rats.J Biochem (Tokyo). 1984; 96: 1705-1712Crossref PubMed Scopus (26) Google Scholar, 28Hayward D. Schiff D. Fedunec S. Chan G. Davis P.J. Poznansky M.J. Bilirubin diffusion through lipid membranes.Biochim Biophys Acta. 1986; 860: 149-153Crossref PubMed Scopus (27) Google Scholar] (albumin and apolipoprotein D in plasma and ligandin in the cytosol). Thus, membranes, including those comprising the blood–brain barrier, do not appear to be a significant barrier to the entry of UCB into cells. The passive diffusion of UCB across the blood–brain barrier is countered by the metabolism of UCB and active secretion of UCB (and/or its metabolites) into the plasma by the brain capillary endothelium [3Ostrow J.D. Pascolo L. Brites D. Tiribelli C. Molecular basis of bilirubin-induced neurotoxicity.Trends Mol Med. 2004; 10: 65-70Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 30Wennberg R.P. The blood–brain barrier and bilirubin encephalopathy.Cell Mol Neurobiol. 2000; 20: 97-109Crossref PubMed Scopus (67) Google Scholar]. Inferior function of these systems, rather than enhanced passive permeability of the blood–brain barrier to UCB, probably contributes to the enhanced risk of neurotoxicity in the newborn compared with adults [[30]Wennberg R.P. The blood–brain barrier and bilirubin encephalopathy.Cell Mol Neurobiol. 2000; 20: 97-109Crossref PubMed Scopus (67) Google Scholar], and in some strains of jaundiced Gunn rats as compared with others [[31]Stobie P.E. Hansen C.T. Hailey J.R. Levine R.L. A difference in mortality between two strains of jaundiced rats.Pediatrics. 1991; 87: 88-93PubMed Google Scholar]. Dora Brites, University of Lisbon, Lisbon, Portugal. CNS cells exposed to UCB in vitro show mixed features of necrosis and apoptosis [32Silva R.F.M. Rodrigues C.M.P. Brites D.T. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin.Pediatr Res. 2002; 51: 535-541Crossref PubMed Scopus (85) Google Scholar, 33Silva R.F.M. Rodrigues C.M.P. Brites D.T. Bilirubin-induced apoptosis in cultured rat neural cells is aggravated by chenodeoxycholic acid but prevented by ursodeoxycholic acid.J Hepatol. 2001; 34: 402-408Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar], with oxidative stress, damage to plasma membranes and mitochondria, and cytokine release all playing a role. The common denominator is rapid induction by UCB of oxidative damage to neuronal plasma membranes, resulting in changes in phospholipid and protein structure [34Rodrigues C.M. Sola S. Castro R.E. Laires P.A. Brites D. Moura J.J. Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis.J Lipid Res. 2002; 43: 885-894PubMed Google Scholar, 35Brito M.A. Brites D. Butterfield D.A. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes.Brain Res. 2004; 1026: 33-43Crossref PubMed Scopus (75) Google Scholar]. Within 10–15 min of exposure of astrocytes to modestly supersaturating Bf levels, there is release of glutamate [[36]Fernandes A. Silva R.F. Falcao A.S. Brito M.A. Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS.J Neuroimmunol. 2004; 153: 64-75Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar] and glutamate uptake is decreased by about 40% [[37]Silva R.F.M. Mata L.R. Gulbenkian S. Brito M.A. Tiribelli C. Brites D.T. Inhibition of glutamate uptake by unconjugated bilirubin in cultured rat astrocytes: Role of concentration and pH.Biochem Biophys Res Commun. 1999; 265: 67-72Crossref PubMed Scopus (78) Google Scholar]. In cell cultures: (i) UCB causes greater LDH release and apoptosis in neurons, but greater impairment of mitochondrial function (MTT test) and glutamate uptake in astrocytes [[32]Silva R.F.M. Rodrigues C.M.P. Brites D.T. Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin.Pediatr Res. 2002; 51: 535-541Crossref PubMed Scopus (85) Google Scholar]; (ii) young neurons and astrocytes are more vulnerable to UCB toxicity than more differentiated cells [[38]Rodrigues C.M.P. Sola S. Silva R.F.M. Brites D.T. Aging confers different sensitivity to the neurotoxic properties of unconjugated bilirubin.Pediatr Res. 2002; 51: 112-118Crossref PubMed Scopus (27) Google Scholar] (Fig. 1). UCB causes neuronal apoptosis, at least in part, via the mitochondrial pathway, inducing cytochrome c release and depolarization of mitochondria, associated with caspase-3 activation, poly(ADP-ribose) polymerase (PARP) cleavage, and Bax translocation [[39]Rodrigues C.M.P. Sola S. Brites D.T. Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons.Hepatology. 2002; 35: 1186-1195Crossref PubMed Scopus (119) Google Scholar]. Activation by UCB of the cell surface death receptor (Tumor Necrosis Factor Receptor 1, TNFR1) [[40]Fernandes A. Silva R.F. Falcao A.S. Brito M.A. Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS.J Neuroimmunol. 2004; 153: 64-75Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar], leading to activation of p38 Map-Kinase [[41]Lin S. Yan C. Wei X. Paul S.M. Du Y. p38 MAP kinase mediates bilirubin-induced neuronal death of cultured rat cerebellar granule neurons.Neurosci Lett. 2003; 353: 209-212Crossref PubMed Scopus (19) Google Scholar] and accumulation of intracellular calcium [[35]Brito M.A. Brites D. Butterfield D.A. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes.Brain Res. 2004; 1026: 33-43Crossref PubMed Scopus (75) Google Scholar], suggests that the extrinsic apoptotic pathway is involved also. Cytokine release is also important. Exposure of cultured astrocytes to UCB at Bf modestly above saturation acutely stimulates secretion of Tumor Necrosis Factor-α (TNF-α) and Interleukine-1β (IL-1β), but suppresses IL-6 release [[40]Fernandes A. Silva R.F. Falcao A.S. Brito M.A. Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS.J Neuroimmunol. 2004; 153: 64-75Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. Responses of neurons are over 90% lower [[42]Falcao A.S. Fernandes A. Brito M.A. Silva R.F. Brites D. Younger astrocytes are more prone to bilirubin-induced inflammatory response, glutamate release and cell death that older cultures.4th Forum of European Neuroscience (FENS Forum), 359A. 2004Google Scholar]. The UCB-mediated cytokine release is associated with TNFR1 activation, which induces translocation to the nucleus of the transcription factor, NF-κB [[40]Fernandes A. Silva R.F. Falcao A.S. Brito M.A. Brites D. Cytokine production, glutamate release and cell death in rat cultured astrocytes treated with unconjugated bilirubin and LPS.J Neuroimmunol. 2004; 153: 64-75Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar]. Interleukine 10 (IL-10) and glycoursodeoxycholate (GUDC) suppress UCB-induced release of IL-1β and TNF-α by astrocytes. While IL-10 acts by blocking activation of NF-κB, the GUDC mechanism seems not to involve this pathway [[43]Fernandes A. Falcao A.S. Silva R.F. Brito M.A. Brites D. Glycoursodeoxycholate and IL-10 as modulators of the toxic and immunostimulator effects of bilirubin in astrocytes.Falk Symp. 2003; 138 ([Abstract]): 63Google Scholar]. M.A. Brito, University of Lisbon, Lisbon, Portugal reported that exposure of synaptosomal vesicles from gerbil cortex to 100 nM UCB or 300 μM H2O2 for 4 h led to 10–25% increases of: intravesicular calcium, ROS, lipid peroxides, protein carbonyls, and the oxidized/reduced glutathione (GSSG/GSH) ratio, accompanied by decreases in membrane-bound Mg2+ ATP-ase and Na+/K+ ATP-ase activities [[35]Brito M.A. Brites D. Butterfield D.A. A link between hyperbilirubinemia, oxidative stress and injury to neocortical synaptosomes.Brain Res. 2004; 1026: 33-43Crossref PubMed Scopus (75) Google Scholar]. Gianluca Tell, University of Udine, Udine, Italy. Cellular reduction/oxidation (redox) status regulates several aspects of cellular function [[44]Nakamura H. Nakamura K. Yodoi J. Redox regulation of cellular activation.Annu Rev Immunol. 1997; 15: 351-369Crossref PubMed Scopus (952) Google Scholar]. 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These ‘redox sensors’, which are activated by breaking or formation of intramolecular –S–S– bonds, include the rapidly activated peroxyredoxins (PrxI, PrxII and PrxVI), and the late-activated nuclear protein Apurinic Apyrimidinic Endonuclease/Redox Effector Factor 1 (APE/Ref-1) [47Dalle-Donne I. Scaloni A. Giustarini D. Cavarra E. Tell G. Lungarella G. et al.Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics.Mass Spectrom Rev. 2005; 24: 55-99Crossref PubMed Scopus (336) Google Scholar, 48Paron I. D'Elia A. D'Ambrosio C. Scaloni A. D'Aurizio F. Prescott A. et al.A proteomic approach to identify early molecular targets of oxidative stress in human epithelial lens cells.Biochem J. 2004; 378: 929-937Crossref PubMed Scopus (91) Google Scholar]. APE/Ref-1 has endonuclease DNA repair and nuclear redox activity, through activation of redox-sensitive transcription factors, such as Activator Protein-1 (AP-1) and Early Growth Response protein-1 (Egr-1), that control the expression of antioxidant enzymes [[47]Dalle-Donne I. Scaloni A. Giustarini D. Cavarra E. Tell G. Lungarella G. et al.Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics.Mass Spectrom Rev. 2005; 24: 55-99Crossref PubMed Scopus (336) Google Scholar]. UCB, an abundant endogenous antioxidant [19Dore S. Snyder S.H. Neuroprotective action of bilirubin against oxidative stress in primary hippocampal cultures.Ann NY Acad Sci. 1999; 890: 167-172Crossref PubMed Scopus (68) Google Scholar, 21Stocker R. Yamamoto Y. McDonagh A.F. Glazer A.N. Ames B.N. Bilirubin is an antioxidant of possible physiological importance.Science. 1987; 235: 1043-1046Crossref PubMed Scopus (2661) Google Scholar], functions as a direct ROS scavenger. New studies suggest that UCB also functions at the genomic level. Exposure of HeLa and HepG2 cells to non-toxic levels of UCB (Bf=50 nM), rapidly increases phosphorylation of Extracellular Signal Regulated Kinase (ERK2), mediating an increase in APE/Ref-1 expression and DNA-binding of AP-1 and Egr-1. Thus, at physiological levels, UCB also stimulates other antioxidant functions of cells. Steven M. Shapiro, Virginia Commonwealth University, Richmond, VA, USA. Glutamate is the primary excitatory neurotransmitter in the brain [[49]Kandel E.R. Schwartz J.H. Jessell T.M. Principles of neural science.4th ed. McGraw-Hill, New York2000Google Scholar]. Among the four glutamate receptors, the N-methyl-D-aspartate (NMDA) sub-type is ion channel coupled, and requires depolarization of the cell to release a magnesium ion block of the channel, allowing calcium ions to enter the cell [[49]Kandel E.R. Schwartz J.H. Jessell T.M. Principles of neural science.4th ed. McGraw-Hill, New York2000Google Scholar]. When certain regions the brain are exposed to excess glutamate (e.g. during seizures or ischemia), the NMDA channel is over-activated and calcium pours into the cytosol; this can be prevented by blocking calcium entry with the NMDA channel antagonist, MK-801 [[50]Churn S.B. Multifunctional calcium and calmodulin-dependent kinase II in neuronal function and disease.Adv Neuroimmunol. 1995; 5: 241-259Abstract Full Text PDF PubMed Scopus (24) Google Scholar]. The cell compensates in part by uptake of calcium into intracellular organelles including mitochondria, but this disrupts the electro-chemical potential across the inner mitochondrial membrane, inhibits ATP production, and leads to cell apoptosis. [[49]Kandel E.R. Schwartz J.H. Jessell T.M. Principles of neural science.4th ed. McGraw-Hill, New York2000Google Scholar]. There are studies that argue for [51Hoffman D.J. Zanelli S.A. Kubin J. Mishra O.P. Delivoria-Papadopoulos M. The in vivo effect of bilirubin on the N-methyl-D-aspartate receptor/ion channel complex in the brains of newborn piglets.Pediatr Res. 1996; 40: 804-808Crossref PubMed Scopus (64) Google Scholar, 52McDonald 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. 1998; 150: 21-29Crossref PubMed Scopus (100) Google Scholar, 53Grojean S. Koziel V. Vert P. Daval J.L. 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Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model.Exp Neurol. 1998; 150: 21-29Crossref PubMed Scopus (100) Google Scholar]; evidence that this injury is caused by an NDMA receptor-mediated excitoxic mechanism needs to be confirmed with quantitative analyses. MK-801 is not, however, protective against UCB-induced cell death in cultured hippocampal cells [[55]Shapiro S.M. Reversible brainstem auditory evoked potential abnormalities in jaundiced Gunn rats given sulfonamide.Pediatr Res. 1993; 34: 629-633Crossref PubMed Scopus (34) Google Scholar], or in jaundiced Gunn rats (Shapiro S, personal observation). Alternatively, UCB might act by impairing intracellular calcium homeostasis, which is the principal mechanism of neuronal cell death in models of global ischemia [[56]Churn S.B. Taft W.C. DeLorenzo R.J. 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• W2100804518 created "2016-06-24" @default.
• W2100804518 creator A5020748511 @default.
• W2100804518 creator A5071646464 @default.
• W2100804518 date "2005-07-01" @default.
• W2100804518 modified "2023-09-24" @default.
• W2100804518 title "The molecular basis of bilirubin encephalopathy and toxicity: Report of an EASL Single Topic Conference, Trieste, Italy, 1–2 October, 2004" @default.
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