Rates of Bilirubin Clearance from Rat Brain Regions

Hansen, Thor Willy Ruud; Cashore, William J.

doi:10.1159/000244229

Cited by 18 publications

(18 citation statements)

References 13 publications

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“…The half-life of bilirubin found in this study (18.5 ± 28.3 min in the control group) is very close to the half-life of 16.1 ± 7.7 and 18.5 ± 21.5 min, respectively, found in two previous studies [14,45]. In those studies pHJ-bilirubin was used, raising the possibility of underestimating the rate of clearance.…”

Section: Brain Bilirubin In Hemolytic Anemiasupporting

confidence: 87%

Hemolytic Anemia Does Not Increase Entry into, nor Alter Rate of Clearance of Bilirubin from Rat Brain

Hansen¹,

Allen²

1996

Neonatology

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The risk of bilirubin encephalopathy is believed to be increased in hemolytic relative to nonhemolytic jaundice. Young SPRD rats were injected with either acetylphenylhydrazine (APHZ, n = 22) 75 mg/kg or an equivalent volume of the solvent (control, n = 22) intraperitoneally for 3 successive days. One the 4th day, hyperbilirubinemia was induced by a 5-min intravenous infusion of 50 mg/kg bilirubin. After sacrifice (at 10 or 60 min) the brain vessels were flushed in situ with ice-cold saline. Serum bilirubin was 600 ± 108 μmol/l (mean ± SD) at 10 min, and 295 ± 98 μmol/l at 60 min. Hematocrit was significantly reduced in the APHZ rats versus controls (26 ± 3 vs. 41 ± 3, p < 0.0001). The concentration of bilirubin in brain was determined by acid chloroform extraction and diazotization. The brain bilirubin values were 5.5 ± 1.5 versus 5.4 ± 2.1 mmol/gat 10 min (APHZ vs. control), and 1.3 ± 0.6 versus 0.8 ± 0.7 nmol/g at 60 min. The half-life of bilirubin in brain was calculated with an exponential fitting program. The half-life of bilirubin in brain for the two groups was 24.3 ± 21.9 versus 18.5 ± 28.3 min. There were no significant differences between the groups in either of these measures. We conclude that in young rats, hemolytic anemia does not increase the acute entry of bilirubin into brain, nor does it affect the clearance of bilirubin from brain.

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Section: Brain Bilirubin In Hemolytic Anemiasupporting

confidence: 87%

Hemolytic Anemia Does Not Increase Entry into, nor Alter Rate of Clearance of Bilirubin from Rat Brain

Hansen¹,

Allen²

1996

Neonatology

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“…Thus, the experimental conditions used in our experiments were patterned on those previously shown to result in significant bilirubin concentrations in the brain. Under similar conditions the half-life of bilirubin in whole brain has been between 16.1 Ϯ 7.7 (13) and 18 Ϯ 21.5 min (mean Ϯ SD) (10). Similarly, the half-life in hippocampus has been 17.1 Ϯ 8.9 (13) to 19.0 Ϯ 21.5 min (10).…”

Section: Bilirubin Inhibits Ltp In Rat Brainmentioning

confidence: 87%

“…The observation time in our experiments was therefore equivalent to 6 -7 half-lives, suggesting that there may be residual effects of bilirubin neurotoxicity at a time when only minimal amounts of bilirubin remain in the brain. Previous studies found that bilirubin can be detected in the brain at 15 min after administration (10,13). Although the brain bilirubin concentrations have not been quantitatively measured in our study, we started our electrophysiological observation 1 min after bilirubin infusion and had actually noted significant effects on PS as well as on LTP.…”

Section: Bilirubin Inhibits Ltp In Rat Brainmentioning

confidence: 88%

“…Although the brain bilirubin concentrations have not been quantitatively measured in our study, we started our electrophysiological observation 1 min after bilirubin infusion and had actually noted significant effects on PS as well as on LTP. It seems likely that small amounts of bilirubin start to enter the brain shortly after infusion of bilirubin is begun, and well before the 15-min time point where brain bilirubin was measured in previous studies (10,13).…”

Section: Bilirubin Inhibits Ltp In Rat Brainmentioning

confidence: 90%

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The Effects of Bilirubin on Evoked Potentials and Long-Term Potentiation in Rat Hippocampus In Vivo

2003

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Neonatal jaundice is a common condition that could potentially lead to severe neurotoxicity. In this electrophysiological study we observed the effects of a short-term bilirubin injection on evoked potentials (population spike, PS) and long-term potentiation (LTP) in the hippocampal CA 3 region of Sprague Dawley rats in vivo. The animal received a bolus i.v. injection of either 60 mg/kg, or 30 mg/kg of bilirubin, or an equivalent volume of bilirubin-free vehicle in 5 min. The results showed that both bilirubin-treated groups had a dose-independent prolongation of peak latencies and decrease of slopes of the PS at all measured time points following injection (1, 3, 5, 10, 15, 30, 45, 60, 90, 120 min), while the amplitudes of the PS did not change significantly. The peak latency, slope, and the amplitude of PS stayed unchanged in the control group. Furthermore, while LTP could be induced by high-frequency stimulation in control animals, this phenomenon was absent in both bilirubin-treated groups. The amplitudes of the PS in the two treated groups after stimulation were also smaller than those of the control animals at every time points. These findings are in accordance with previous observations showing significant depressive effects of bilirubin on the nervous system. Our novel finding that short-term exposure to bilirubin can inhibit the induction of LTPs in the hippocampus, is compatible with the suggestion that neonatal hyperbilirubinemia can impact on learning and memory. Hyperbilirubinemia is a common phenomenon in the neonatal period, and attracts a lot of attention due to its potential for neurotoxicity (1). Recent studies have shown that bilirubin may exert effects on neurons via multiple mechanisms including inhibition of protein phosphorylation (2) and release of neurotransmitters (3). However, these studies were carried out in vitro, and the results provide limited information on the sustained effects of bilirubin in the body.Long-term potentiation (LTP) was first documented in the dentate gyrus of rabbit hippocampi by Bliss et al. (4). They stimulated the perforant path (PP) at each observed time point by high-frequency electricity with a given frequency and strength. Following this, single stimulation would significantly and lastingly increase the PS in the dentate gyrus as well as the so-called population excitatory postsynaptic potential (pEPSP). This phenomenon was called LTP and has also been observed in other parts of hippocampus. LTP in the hippocampus is now considered as an important parameter related to learning and memory (5).An investigation of the correlation between bilirubin and LTP might contribute to elucidating the mechanism of bilirubin neurotoxicity and perhaps in understanding the long-term effects of bilirubin encephalopathy. We hypothesized that bilirubin neurotoxicity may affect individual neuronal functions in distinctive ways and with variable degrees of reversibility. In this in vivo electrophysiological study, we observed the effects of an i.v. bilirubin bolus on the evoke...

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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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confidence: 99%

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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Rates of Bilirubin Clearance from Rat Brain Regions

Cited by 18 publications

References 13 publications

Hemolytic Anemia Does Not Increase Entry into, nor Alter Rate of Clearance of Bilirubin from Rat Brain

Hemolytic Anemia Does Not Increase Entry into, nor Alter Rate of Clearance of Bilirubin from Rat Brain

The Effects of Bilirubin on Evoked Potentials and Long-Term Potentiation in Rat Hippocampus In Vivo

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

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