Elevated Levels of Bilirubin and Long-Term Exposure Impair Human Brain Microvascular Endothelial Cell Integrity

Palmela, Inês; Cardoso, Fernanda C.; Bernas, Michael; Correia, Leonor; Vaz, Ana Rita; Silva, Rui F. M.; Fernandes, Adelaide; Kim, Kwang S.; Brites, Dora; Brito, Maria Alexandra

doi:10.2174/156720211795495358

Cited by 37 publications

(57 citation statements)

References 118 publications

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“…The pathogenesis of encephalopathy by unconjugated bilirubin is poorly understood but it seems to involve oxidative stress, a disruption of the blood–brain barrier and the consequent damage of neuronal cells (Palmela et al, 2011). Brain pathology typically following bilirubin neurotoxicity has been suggested to involve the basal ganglia, particularly globus pallidus, as well as subthalamic nuclei, hippocampus, diencephalon, midbrain, pontine and brain stem nuclei and cerebellum (Johnson & Bhutani, 2011; Koziol, Budding & Chidekel, 2013), locations which take part in a wide variety of motor, sensory and cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

“…While it is at present reasonably well controlled in the developed countries, it is still a concern in economically compromised areas (Sgro, Campbell & Shah, 2006; Kaplan, Bromiker & Hammerman, 2011). The pathogenesis of encephalopathy by unconjugated bilirubin is poorly understood but neuronal damage may be linked to oxidative stress and a disruption of the blood–brain barrier (Palmela et al, 2011). Kernicterus refers to the severe neurodevelopmental consequences, but more subtle forms of bilirubin encephalopathy also exist (Shapiro, 2003; Johnson & Bhutani, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study

Hokkanen

Launes

Michelsson

2014

PeerJ

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Background. Neonatal hyperbilirubinemia (HB) may cause severe neurological damage, but serious consequences are effectively controlled by phototherapy and blood exchange transfusion. HB is still a serious health problem in economically compromised parts of the world. The long term outcome has been regarded favorable based on epidemiological data, but has not been confirmed in prospective follow-up studies extending to adulthood.Methods. We studied the long term consequences of HB in a prospective birth cohort of 128 HB cases and 82 controls. The cases are part of a neonatal at-risk cohort (n = 1196) that has been followed up to 30 years of age. HB cases were newborns ≥ 2500 g birth weight and ≥ 37 weeks of gestation who had bilirubin concentrations > 340 µmol/l or required blood exchange transfusion. Subjects with HB were divided into subgroups based on the presence (affected HB) or absence (unaffected HB) of diagnosed neurobehavioral disorders in childhood, and compared with healthy controls. Subjects were seen at discharge, 5, 9 and 16 years of life and parent’s and teacher’s assessments were recorded. At 30 years they filled a questionnaire about academic and occupational achievement, life satisfaction, somatic and psychiatric symptoms including a ADHD self-rating score. Cognitive functioning was tested using ITPA, WISC, and reading and writing tests at 9 years of life.Results. Compared to controls, the odds for a child with HB having neurobehavioral symptoms at 9 years was elevated (OR = 4.68). Forty-five per cent of the HB group were affected by cognitive abnormalities in childhood and continued to experience problems in adulthood. This was apparent in academic achievement (p < 0.0001) and the ability to complete secondary (p < 0.0001) and tertiary (p < 0.004) education. Also, the subgroup of affected HB reported persisting cognitive complaints e.g., problems with reading, writing and mathematics. Childhood symptoms of hyperactivity/impulsivity (p < 0.0001) and inattention (p < 0.02) were more common in HB groups, but in adulthood the symptoms were equal. The affected HB had lower scores in parameters reflecting life satisfaction, less controlled drinking, but not increased substance abuse.Discussion. Our results indicate that neonatal HB has negative consequences in adult age. A prospectively collected cohort with strict inclusion criteria enables to control most of the bias factors involved with retrospective data. The control and HB groups were remarkably similar at birth in terms of medical data, and the growth environment of the children, as well as the parents’ social groups, education, size of family, type of housing at birth and at 9 years of age. Our findings bear resemblance to disorders of the fronto-striatal network, and also symptoms of the ADHD spectrum were frequent in the HB group suggesting a link of HB to other neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study

Hokkanen

Launes

Michelsson

2014

PeerJ

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“…Longer durations of hyperbilirubinemia compromise vascular endothelial dynamics by increasing oxidative stress, cytokine release, cell detachment,[1718] and angiogenic sprouting. Individually, and in combination, these factors facilitate passage of bilirubin from the blood into brain and aggravate bilirubin neurotoxicity.…”

Section: Risk Of Neural Impairment In Vulnerable Newborns: Bench Studiesmentioning

confidence: 99%

Bilirubin neurotoxicity in preterm infants: Risk and prevention

Bhutani

Wong

2013

J Clin Neonatol

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Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% in babies <30, 31-32, and 33-34 wks gestational age, respectively. Phototherapy initiated at 24±12 hr effectively prevented hyperbilirubinemia in infants <2,000 g even in the presence of hemolysis. This approach (in 1985) reduced exchange transfusions from 23.9% to 4.8%. Now with 3 decades of experience in implementing effective phototherapy, the need for exchange transfusions has virtually been eliminated. However, bilirubin neurotoxicity continues to be associated with prematurity alone. The ability to better predict this risk, other than birthweight and gestation, has been elusive. Objective tests such as total bilirubin, unbound or free bilirubin, albumin levels, and albumin-bilirubin binding, together with observations of concurrent hemolysis, sepsis, and rapid rate of bilirubin rise have been considered, but their individual or combined predictive utility has yet to be refined. The disruptive effects of immaturity, concurrent neonatal disease, cholestasis, use of total parenteral nutrition or drugs that alter bilirubin-binding abilities augment the clinical risk of neurotoxicity. Current management options rely on the “fine-tuning” of each infant's exposure to beneficial antioxidants and avoidance of silent neurotoxic properties of bilirubin navigated within the safe spectrum of operational thresholds demarcated by experts.

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“…These high levels of UCB become neurotoxic by inducing oxidative and nitrosative stress, mainly in neurons [23], [24], and the release of pro-inflammatory cytokines by astrocytes [25] and microglia [26]. Our most recent studies revealed that human BMEC exposed to UCB are also under nitrosative stress, as indicated by the upregulation of endothelial nitric oxide synthase and production of nitrites, the end-product of nitric oxide, and release cytokines, such as the vascular endothelial growth factor and interleukin (IL)-6 [27]. Interestingly, both nitric oxide and these cytokines are known to increase BBB permeability [28], [29].…”

Section: Introductionmentioning

confidence: 99%

Exposure to Lipopolysaccharide and/or Unconjugated Bilirubin Impair the Integrity and Function of Brain Microvascular Endothelial Cells

et al. 2012

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BackgroundSepsis and jaundice are common conditions in newborns that can lead to brain damage. Though lipopolysaccharide (LPS) is known to alter the integrity of the blood-brain barrier (BBB), little is known on the effects of unconjugated bilirubin (UCB) and even less on the joint effects of UCB and LPS on brain microvascular endothelial cells (BMEC).Methodology/Principal FindingsMonolayers of primary rat BMEC were treated with 1 µg/ml LPS and/or 50 µM UCB, in the presence of 100 µM human serum albumin, for 4 or 24 h. Co-cultures of BMEC with astroglial cells, a more complex BBB model, were used in selected experiments. LPS led to apoptosis and UCB induced both apoptotic and necrotic-like cell death. LPS and UCB led to inhibition of P-glycoprotein and activation of matrix metalloproteinases-2 and -9 in mono-cultures. Transmission electron microscopy evidenced apoptotic bodies, as well as damaged mitochondria and rough endoplasmic reticulum in BMEC by either insult. Shorter cell contacts and increased caveolae-like invaginations were noticeable in LPS-treated cells and loss of intercellular junctions was observed upon treatment with UCB. Both compounds triggered impairment of endothelial permeability and transendothelial electrical resistance both in mono- and co-cultures. The functional changes were confirmed by alterations in immunostaining for junctional proteins β-catenin, ZO-1 and claudin-5. Enlargement of intercellular spaces, and redistribution of junctional proteins were found in BMEC after exposure to LPS and UCB.ConclusionsLPS and/or UCB exert direct toxic effects on BMEC, with distinct temporal profiles and mechanisms of action. Therefore, the impairment of brain endothelial integrity upon exposure to these neurotoxins may favor their access to the brain, thus increasing the risk of injury and requiring adequate clinical management of sepsis and jaundice in the neonatal period.

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Elevated Levels of Bilirubin and Long-Term Exposure Impair Human Brain Microvascular Endothelial Cell Integrity

Cited by 37 publications

References 118 publications

Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study

Adult neurobehavioral outcome of hyperbilirubinemia in full term neonates—a 30 year prospective follow-up study

Bilirubin neurotoxicity in preterm infants: Risk and prevention

Exposure to Lipopolysaccharide and/or Unconjugated Bilirubin Impair the Integrity and Function of Brain Microvascular Endothelial Cells

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