Bilirubin-Induced Changes in Brain Energy Metabolism after Osmotic Opening of the Blood-Brain Barrier

Wennberg, Richard P.; Johansson, Barbro; Folbergrová, Jaroslava; Siesjö, Bo K.

doi:10.1203/00006450-199111000-00015

Cited by 37 publications

(7 citation statements)

References 19 publications

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“…Hypernatremia can cause disruption in the bloodbrain barrier, which facilitates the diffusion of bilirubin across the blood-brain barrier and thereby may enhance the risk of bilirubin encephalopathy. 33 Hypernatremia and hyperbilirubinemia each cause central nervous system depression among infants with lethargy, poor suck, and anorexia. 34,35 These factors can lead to a cycle of worsening dehydration, jaundice, and hypernatremia, which in combination can lead to brain injury.…”

Section: Discussionmentioning

confidence: 99%

Breastfeeding-Associated Hypernatremia: Are We Missing the Diagnosis?

Manole²,

et al. 2005

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ABSTRACT. Objectives. To assess the incidence and complications of breastfeeding-associated hypernatremic dehydration among hospitalized neonates.Study Design. A retrospective study was conducted at Children's Hospital of Pittsburgh over a 5-year period, to identify otherwise healthy term and near-term (>35 weeks of gestation) breastfed neonates (<29 days of age) who were admitted with serum sodium concentrations of >150 mEq/L and no explanation for hypernatremia other than inadequate milk intake.Results. The incidence of breastfeeding-associated hypernatremic dehydration among 3718 consecutive term and near-term hospitalized neonates was 1.9%, occurring for 70 infants. These infants were born primarily to primiparous women (87%) who were discharged within 48 hours after birth (90%). The most common presenting symptom was jaundice (81%). Sixty-three percent of infants underwent sepsis evaluations with lumbar puncture. No infants had bacteremia or meningitis. Infants had hypernatremia of moderate severity (median: 153 mEq/L; range: 150 -177 mEq/L), with a mean weight loss of 13.7%. Nonmetabolic complications occurred for 17% of infants, with the most common being apnea and/or bradycardia. There were no deaths. Diseases, Ninth Revision, Clinical Modification; MWH, Magee-Womens Hospital. T he benefits of breastfeeding to children are well established and include decreased incidence of a wide variety of acute infections and chronic diseases, as well as improved neurodevelopmental outcomes. 1,2 A serious potential complication of insufficient breastfeeding is severe hypernatremic dehydration. 3 Neonatal hypernatremic dehydration results from inadequate transfer of breast milk from mother to infant. Furthermore, poor milk drainage from the breasts results in persistence of high milk sodium concentrations. 4 This may exacerbate neonatal hypernatremia. 5,6 We refer to this as "breastfeeding-associated hypernatremia," with the clear understanding that this results only when breastfeeding is not properly established. Hypernatremic dehydration is assumed to be a rare complication of breastfeeding, 7 but recent reports have suggested that the incidence is increasing. [8][9][10][11] The failure to diagnose hypernatremic dehydration can have serious consequences, including seizures, intracranial hemorrhage, 12 vascular thrombosis, 13 and death. 14,15 The purpose of this study was to assess the incidence and complications of breastfeeding-associated hypernatremia among hospitalized neonates at a large pediatric tertiary care center in the United States. Conclusion. Hypernatremic dehydration requiring ABBREVIATIONS. ICD-9-CM, International Classification of METHODSChildren's Hospital of Pittsburgh is a 235-bed freestanding hospital with ϳ12 000 admissions per year. After approval was obtained from the institutional review board, a retrospective study was conducted to identify otherwise healthy term and near-term (gestation of Ն35 weeks) neonates admitted during a 5-year period with serum sodium concentrations of Ն150 mEq/L...

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Section: Discussionmentioning

confidence: 99%

Breastfeeding-Associated Hypernatremia: Are We Missing the Diagnosis?

Manole²,

et al. 2005

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“…Most notable is its ability to uncouple oxidative phosphorylation in isolated mitochondria, 43 and to produce profound decreases in brain energy metabolites. 44,45 Contributing to the uncertainty regarding mechanisms of bilirubin cytotoxicity, most studies were performed using excessively high concentrations of unbound unconjugated bilirubin, frequently of an unpurified commercial source.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons

2002

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Increased levels of unconjugated bilirubin, the end-product of heme catabolism, are detrimental to the central nervous system. To examine the role of apoptosis in bilirubin-induced toxicity and to characterize the biochemical pathway of cell death, we exposed developing rat brain neurons to purified unconjugated bilirubin at concentrations below and above saturation of human serum albumin. Isolated neurons treated with bilirubin showed increased levels of apoptosis. Mitochondrial cytochrome c was extensively released and accumulated in cytosol. Consistent with this observation, caspase-3 was activated and the full-length substrate poly(ADP)ribose polymerase (PARP) degraded, even in the presence of very modestly elevated concentrations of bilirubin. In parallel, all events were prevented in cells preincubated with ursodeoxycholate. Further experiments showed that bilirubin diminished mitochondrial transmembrane potential (⌬⌿ m ) and increased mitochondrial-associated Bax protein levels, while directly disrupting membrane lipid and protein structure. In conclusion, bilirubin induces mitochondrial depolarization and Bax translocation via physical interaction with membranes, mediating the mitochondrial pathway of apoptosis in neurons exposed to bilirubin. These results provide a novel insight into the mechanism of bilirubininduced toxicity.

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“…Whether the lipophilicity of bilirubin plays any role in this context cannot be ascertained by the present data. The very high concentration of bilirubin relative to protein in cytoplasm, ribosomes, and mitochondria in the hyperosmolar group are also notable in light of data from hyperbilirubinemic animals in which changes in electrophysiology or energy metabolism only appeared after hyperosmolar opening of the blood-brain barrier (25). It is also noteworthy that data from a study on short-term bilirubin entry into whole brain did not show an increase during hyperosmolality relative to control conditions, although bilirubin clearance from brain was significantly delayed (22).…”

Section: Discussionmentioning

confidence: 96%

Subcellular Localization of Bilirubin in Rat Brain after In Vivo i.v. Administration of [3H]Bilirubin

2001

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Bilirubin appears to be toxic in vitro to several cellular functions localized to different subcellular compartments. It would therefore be useful to know what concentrations of bilirubin might be found in cell organelles in vivo. Rats were anesthetized and allocated to one of three groups: control, hypercarbia, and hyperosmolality. Each rat received a 5-min bolus dose of bilirubin 50 mg/kg i.v. (containing approximately 200 Ci [ 3 H]bilirubin). Rats were killed 10 or 30 min after the start of the bilirubin infusion. Each brain was homogenized, and subcellular fractions were isolated by high-speed gradient centrifugation in sucrose media. The gradients were separated into aliquots of 2 mL, and the protein content was determined in each aliquot. Radioactivity was determined by scintillation counting, and the content of bilirubin per milligram of protein was calculated. Statistical comparisons were performed with KruskalWallis nonparametric ANOVA. There were highly significant differences in bilirubin content per milligram of protein among subcellular compartments in all groups and at both time points. In all groups there were relatively high concentrations of bilirubin in the myelin fraction, an interesting observation in light of the theory that membranes are the primary target of bilirubin toxicity. The very high concentration of bilirubin relative to protein in cytoplasm, ribosomes, and mitochondria in the hyperosmolar group are also notable in light of data from hyperbilirubinemic animals in which changes in electrophysiology or energy metabolism only appeared after hyperosmolar opening of the bloodbrain barrier. The present data may be useful in planning in vitro studies of bilirubin toxicity in cell organelles. Abbreviations: P1, P2, P3, P4, first, second, third, and fourth pellets from sequential density centrifugations S1, S2, S3, S4, first, second, third, and fourth supernatants from sequential density centrifugations Neonatal jaundice is a common and, in most infants, normal physiologic event, which has been discussed in the medical literature for at least a quarter of a millennium (1). Some jaundiced infants exhibit signs of neurotoxicity, which appears to be transitory in the great majority. Exceptionally, bilirubin toxicity may result in death in the newborn period or in survival with severe neurologic sequelae (kernicterus). During the past 50 y considerable research effort has been directed toward the interaction between bilirubin and the brain, as well as the mechanism (or mechanisms) of neurotoxicity.Much has been learned about how bilirubin enters into and is cleared from the brain, but the process that leads to deposition of bilirubin in basal ganglia and other brain regions to create the pattern known as kernicterus (jaundice of the nuclei) is as yet not understood. Also, none of the theories concerning the basic neurobiological mechanism of bilirubin neurotoxicity have been conclusively proven.A number of methodological problems have bedeviled bilirubin researchers and impeded progress. One o...

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Bilirubin-Induced Changes in Brain Energy Metabolism after Osmotic Opening of the Blood-Brain Barrier

Cited by 37 publications

References 19 publications

Breastfeeding-Associated Hypernatremia: Are We Missing the Diagnosis?

Breastfeeding-Associated Hypernatremia: Are We Missing the Diagnosis?

Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons

Subcellular Localization of Bilirubin in Rat Brain after In Vivo i.v. Administration of [3H]Bilirubin

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