ArticleFrontiers in cellular neuroscience2012
Time-dependent dual effects of high levels of unconjugated bilirubin on the human blood-brain barrier lining.
Article in Frontiers in cellular neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- Bilirubin as a predictor of severity and adverse clinical outcomes of acute ischemic stroke: a systematic review and meta-analysis.BMC neurology · 2025Pooled it
- Liver-nervous system axis: pathways, dysregulation, and translational perspectives.Journal of neuroinflammation · 2026Review
- The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network.Antioxidants (Basel, Switzerland) · 2026Review
- Mechanism of Ammonia-Induced Brain Damage in Chinese Striped-Necked Turtle (Mauremys sinensis).Integrative zoology · 2026Article
- Bilirubin in Parkinson's disease: pathogenic mechanisms and therapeutic potentials.Frontiers in neuroscience · 2026Review
- Factors Affecting the Relationship Between Total and Unbound Bilirubin in Preterm and Term Infants.Acta paediatrica (Oslo, Norway : 1992) · 2025Article
- Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM).Cancer gene therapy · 2025Article
- Higher serum bilirubin levels are associated with hemorrhagic transformation after intravenous thrombolysis in acute ischemic Stroke.Frontiers in aging neuroscience · 2023Article
- In Vitro Study of the Blood-Brain Barrier Transport of Natural Compounds Recovered from Agrifood By-Products and Microalgae.International journal of molecular sciences · 2022Article
- Article
- Vascular network expansion, integrity of blood-brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat.Fluids and barriers of the CNS · 2022Article
- Bilirubin Induces Pain Desensitization in Cholestasis by Activating 5-Hydroxytryptamine 3A Receptor in Spinal Cord.Frontiers in cell and developmental biology · 2021Article
- Experimental models assessing bilirubin neurotoxicity.Pediatric research · 2020Review
- Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?Frontiers in physiology · 2020Review
- Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study.European journal of nutrition · 2019Article
- [Role of caspase-1 activation in bilirubin-induced injury in cultured primary rat hippocampal neurons].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2018Article
- Polyphenols journey through blood-brain barrier towards neuronal protection.Scientific reports · 2017Article
- Cystatin C as a potential therapeutic mediator against Parkinson's disease via VEGF-induced angiogenesis and enhanced neuronal autophagy in neurovascular units.Cell death & disease · 2017Article
- Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1Journal of neuroinflammation · 2017Article
- Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging.International journal of molecular sciences · 2016Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In neonatal jaundice, high levels of unconjugated bilirubin (UCB) may induce neurological dysfunction (BIND). Recently, it was observed that UCB induces alterations on brain microvasculature, which may facilitate its entrance into the brain, but little is known about the steps involved. To evaluate if UCB damages the integrity of human brain microvascular endothelial cells (HBMECs), we used 50 or 100 μM UCB plus human serum albumin, to mimic the neuropathological conditions where levels of UCB free species correspond to moderate and severe neonatal jaundice, respectively. Our results point to a biphasic response of HBMEC to UCB depending on time of exposure. The early response includes increased number of caveolae and caveolin-1 expression, as well as upregulation of vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) with no alterations of the paracellular permeability. In contrast, effects by sustained hyperbilirubinemia are the reduction in zonula occludens (ZO)-1 and β-catenin levels and thus of tight junctions (TJ) strands and cell-to-cell contacts. In addition, reduction of the transendothelial electrical resistance (TEER) and increased paracellular permeability are observed, revealing loss of the barrier properties. The 72 h of HBMEC exposure to UCB triggers a cell response to the stressful stimulus evidenced by increased autophagy. In this later condition, the UCB intracellular content and the detachment of both viable and non-viable cells are increased. These findings contribute to understand why the duration of hyperbilirubinemia is considered one of the risk factors of BIND. Indeed, facilitated brain entrance of the free UCB species will favor its parenchymal accumulation and neurological dysfunction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.