Mechanism of Bilirubin Entry into the Brain in an Animal Model

Bratlid, Dag

doi:10.1007/978-1-4684-7517-3_3

Cited by 4 publications

(5 citation statements)

References 18 publications

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“…Bilirubin has long been known to have adverse effects on brain function, primarily through the syndrome known as kernicterus, in which bilirubin de position in the basal ganglia of the brain is associated with either death in the neonatal period, or severe neurodevelopmental sequel ae in the form of choreoathetosis, deafness and mental retardation [2], Studies on the mechanisms of bilirubin entry into brain have shown that bilirubin probably crosses the intact blood-brain bar rier primarily in the unbound or 'free' form, while albumin-bound bilirubin probably en ters the brain only when the blood-brain bar rier is opened [3,4], In experimental studies bilirubin entry into brain has been increased by drugs that displace bilirubin from its albu min binding, thus causing a transient increase in the free bilirubin concentration [5], In creased amounts of bilirubin also enter the brain when brain blood flow is increased [6] and when the blood-brain barrier is opened [7].…”

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Rates of Bilirubin Clearance from Rat Brain Regions

Hansen

Cashore²

1995

Neonatology

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The mechanism for the preferential distribution of bilirubin to basal ganglia (‘kernicterus’) is unknown. We hypothesized that differences in bilirubin clearance rates between brain regions might explain this phenomenon. Bilirubin [30mg/kg over 5 min, with 370-740 kBq (10-20 μCi) tritiated bilirubin] was infused into a peripheral vein in unanesthetized, young Sprague-Dawley rats (n = 36, weight 149 ± 15 g, mean ± SD). After blood sampling, groups of rats were killed at 15, 30, 45, 60, 75, 180, and 360 min with an intravenous injection of pentobarbital. Brain vasculature was flushed in situ and brains dissected into seven regions, which were weighed, dissolved and scintillation counted. Blood was analyzed for bilirubin, albumin, and blood gases. Brain bilirubin concentrations were calculated after determining the specific activity of bilirubin in serum at the time of sacrifice. Bilirubin half-lives in serum and brain regions were (in minutes, mean ± SD): serum 24.6 ± 17.2, whole brain 18.5 ± 21.5, cortex 17.6 ± 19.3, hippocampus 19.0 ± 21.5, striatum 17.1 ± 18.5, midbrain 16.3 ± 18.6, hypothalamus 17.4 ± 21.0, cerebellum 21.6 ± 33.8, medulla 20.0 ± 24.1. There were no significant differences in bilirubin half-lives between regions. The half-life of bilirubin in brain reported here is appreciably shorter than the 1.7 h previously found in rats with opened blood-brain barriers, but appears compatible with data on auditory brainstem response reversibility following exchange transfusion in jaundiced infants. We conclude that bilirubin disappeares rapidly from brains with intact blood-brain barriers. The rates of clearance found in different brain regions in this model cannot explain the kernicterus phenomenon (i.e. preferential staining of basal ganglia and cerebellum).

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Rates of Bilirubin Clearance from Rat Brain Regions

Hansen

Cashore²

1995

Neonatology

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“…Transfer of bilirubin-albumin to the brain of kernicteric human infants has not been demonstrated, and it is unlikely that this process is involved in the type of kernicterus induced by giving sulfonamides. These cases can be explained by competition of drug and pigment for binding to serum albumin (2,9,19,21). Furthermore, different processes of photoisomerisation of bilirubin result from irradiation ofbilirubin with blue light in rat serum albumin solutions and with the human protein (17,20), a finding which explains the excretion of different end products in rats and human infants after irradiation.…”

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Aggregation of Bilirubin in Injectates and Incubation Media: Its Significance in Experimental Studies of CNS Toxicity

Brodersen

Stern

1987

Neuropediatrics

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In experimental work with bilirubin toxicity, incubates or injectates are prepared without added albumin, or with a molar excess of bilirubin over albumin. Bilirubin is liable to aggregation as free bilirubin acid under these circumstances, giving rise to variable toxicity. Stable solutions are obtained with a molar excess of albumin over bilirubin; such solutions show no toxicity, however. It is suggested that this difficulty may be circumvented by using an excess of albumin, adding a sulfonamide as a bilirubin displacer, to provoke toxicity.

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“…Although information is available regarding bilirubin concentrations in whole brain and brain regions during induced hyperbilirubinemia in experimental animals (17)(18)(19)(20)(21)(22), no studies are on record which track bilirubin entry into cells and subcellular compartments in vivo. The purpose herein was to study the subcellular localization of bilirubin in rat brain after in vivo administration of radioactively labeled bilirubin.…”

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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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Mechanism of Bilirubin Entry into the Brain in an Animal Model

Cited by 4 publications

References 18 publications

Rates of Bilirubin Clearance from Rat Brain Regions

Rates of Bilirubin Clearance from Rat Brain Regions

Aggregation of Bilirubin in Injectates and Incubation Media: Its Significance in Experimental Studies of CNS Toxicity

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

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