A Gunn rat model of preterm hyperbilirubinemia

Waddell, Jaylyn; He, Min; Tang, Ningfeng; Rizzuto, Christian; Bearer, Cynthia F.

doi:10.1038/s41390-019-0599-x

Cited by 7 publications

(18 citation statements)

References 26 publications

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“…Two tests were selected specifically for assessing the motor and coordination abilities of young rats, the righting reflex, and the negative geotaxis [86][87][88]. No training was required, and animals were asked to perform each test only one time a day to avoid fatigue.…”

Section: Behavioral Testsmentioning

confidence: 99%

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage

Gazzin

Ben

Montrone

et al. 2020

IJMS

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Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.

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Section: Behavioral Testsmentioning

confidence: 99%

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage

Gazzin

Ben

Montrone

et al. 2020

IJMS

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“…Here we report our findings on the impact of choline supplementation on the bilirubin-induced behavioral alterations exhibited by Gunn rats treated with SDMX on postnatal day 5 (P5) ( 22 ). To mimic the common human condition of choline deficiency ( 29 – 31 ), and to control for the amount of choline in the diets of the dams, we tested Nj and jj pups from dams placed on choline-restricted diets on gestational day 5 (G5).…”

Section: Introductionmentioning

confidence: 99%

“…The prolonged development of the cerebellum renders it extremely vulnerable to perinatal insults ( 12 ). The sensitivity of the developing cerebellum to the neurotoxic effects of bilirubin has been demonstrated in the Gunn rat ( 18 , 19 , 22 ). Homozygous Gunn rats (jj) possess a genetic mutation that leads to the loss of the activity of uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) and as a consequence, concentrations of total serum bilirubin are elevated ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

“…Our laboratory recently began utilizing the Gunn rat, treating them on P5 with sulfadimethoxine (SDMX) to model preterm hyperbilirubinemia ( 22 ). SDMX displaces bilirubin from albumin, acutely increasing levels of Bf ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

“…SDMX displaces bilirubin from albumin, acutely increasing levels of Bf ( 18 ). The administration of SDMX on postnatal day 5 (P5) did not elicit overt signs of bilirubin-induced toxicity but disrupted expression of ultrasonic vocalizations and motor behavior at later ages ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Choline supplementation prevents the effects of bilirubin on cerebellar-mediated behavior in choline-restricted Gunn rat pups

Waddell

Rickman

et al. 2020

Pediatr Res

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Background: Bilirubin is produced by the breakdown of hemoglobin, and is normally catabolized and excreted. Neurotoxic accumulation of serum bilirubin often occurs in premature infants. The homozygous Gunn rat lacks uridine diphosphate-glucuronosyltransferase-1A1 (UGT1A1), the enzyme needed to biotransform bilirubin. This rodent model of hyperbilirubinemia emulates many aspects of bilirubin toxicity observed in the human infant. We demonstrate that choline supplementation in early postnatal development is neuroprotective in the choline restricted Gunn rat, when hyperbilirubinemia is induced on postnatal day 5. Methods: We first compared behaviors and cerebellar weight of pups born to dams consuming regular rat chow to those of dams consuming choline-restricted diets. Secondly, we measured behaviors and cerebellar weights of pups born to choline-restricted dams, reared on a choline-restricted diet, supplemented with or without choline and treated with or without sulfadimethoxine (SDMX). Results: A choline-restricted diet did not change the behavioral outcomes, but cerebellar weight was reduced in the choline-restricted group regardless of genotype or SDMX administration. SDMX induced behavioral deficits in jj pups, and choline supplementation improved most behavioral effects and cerebellar weight in SDMX-treated jj rats. Conclusion: These results suggest that choline may be used as a safe and effective neuroprotective intervention against hyperbilirubinemia in the choline deficient premature infant.

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Yinzhihuang Oral Liquid Ameliorates Hyperbilirubinemia Induced by δ‐Aminolevulinic Acid and Novobiocin in Neonatal Rats

Han

Dai

et al. 2021

Chemistry & Biodiversity

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Yinzhihuang oral liquid (YZH) is a traditional Chinese medicine that has been widely used in Asia to prevent and treat neonatal hyperbilirubinemia, but the published preclinical studies on its anti‐hyperbilirubinemia effect are conducted in adult animals, partly due to the lack of preclinical neonatal hyperbilirubinemia animal models. In the present study, we tested six reagents to induce hyperbilirubinemia in neonatal rats, and established two appropriate neonatal hyperbilirubinemia rat models by subcutaneous injection of δ‐Aminolevulinic acid (ALA, 200 mg/kg) or novobiocin (NOVO, 200 mg/kg). Oral treatment of YZH (80, 160 and 320 mg/kg) significantly decreased serum conjugated bilirubin levels in ALA‐treated neonatal rats and serum unconjugated bilirubin levels in NOVO‐treated neonatal rats, respectively. Additionally, pre‐treatment of YZH also prevented the increase of serum bilirubin levels in both ALA‐ and NOVO‐treated rats. Mechanistically, YZH significantly up‐regulated the mRNA expression of genes involved in hepatic bilirubin disposition (organic anion‐transporting polypeptide 1b2, Oatp1b2; multidrug resistance‐associated protein 2, Mrp2) and bilirubin conjugation (UDP‐glucuronosyltransferase 1a1, Ugt1a1). Additionally, YZH up‐regulated the mRNA expression of cytochrome P450 1A1 (Cyp1a1), the target gene of aryl hydrocarbon receptor (AhR), and increased the nuclear protein levels of AhR in livers of neonatal rats. YZH and its two active ingredients, namely baicalin (BCL) and 4’‐hydroxyacetophenone (4‐HT), up‐regulated the mRNA expression of AhR target genes (CYP1A1 and UGT1A1) and increased nuclear protein levels of AhR in HepG2 cells. In conclusion, the present study provides two neonatal hyperbilirubinemia animal models and evaluates the anti‐hyperbilirubinemia effect and mechanisms of YZH in neonatal animals.

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A Gunn rat model of preterm hyperbilirubinemia

Cited by 7 publications

References 26 publications

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage

Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage

Choline supplementation prevents the effects of bilirubin on cerebellar-mediated behavior in choline-restricted Gunn rat pups

Yinzhihuang Oral Liquid Ameliorates Hyperbilirubinemia Induced by δ‐Aminolevulinic Acid and Novobiocin in Neonatal Rats

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