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Albumin administration protects against bilirubin-induced auditory brainstem dysfunction in Gunn rat pups

Authors

  • Andrea B. Schreuder,

    1. Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, Beatrix Children's Hospital - University Medical Center Groningen, Groningen, the Netherlands
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  • Ann C. Rice,

    1. Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA
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  • Jana Vanikova,

    1. 1st Faculty of Medicine, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University, Prague, Czech Republic
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  • Libor Vitek,

    1. 1st Faculty of Medicine, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University, Prague, Czech Republic
    2. 1st Faculty of Medicine, 4th Department of Internal Medicine, Charles University, Prague, Czech Republic
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  • Steven M. Shapiro,

    1. Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA
    2. Department of Child Neurology, Children's Mercy Hospital, University of Missouri, Kansas City, Missouri, USA
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  • Henkjan J. Verkade

    Corresponding author
    • Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, Beatrix Children's Hospital - University Medical Center Groningen, Groningen, the Netherlands
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Correspondence

Henkjan J. Verkade, MD, PhD, Beatrix Children's Hospital - University Medical Center Groningen,

Hanzeplein 1, 9713 GZ, Groningen, the Netherlands

Tel: + 31 50 36 12470

Fax: + 31 50 36 11671

e-mail: h.j.verkade@umcg.nl

Abstract

Background

Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain.

Aim

To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia.

Methods

We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity.

Results

Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment.

Conclusions

Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations.

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