Bilirubin neurotoxicity: a narrative review on long lasting, insidious, and dangerous effects

Brites, Dora; Silva, Rui F. M.

doi:10.21037/pm-21-37

Cited by 3 publications

(3 citation statements)

References 203 publications

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“…Cells forming the blood–brain interfaces require active oxidative metabolism to maintain their tightness and fulfill their functions of protection towards the maturing brain. These cells are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin, and accordingly cerebral endothelial cells have been considered as targets for bilirubin toxicity (reviewed in [ 16 ]). In vitro, bilirubin was shown to lead to endothelial apoptosis and/or to the secretion of factors that are pro-angiogenic and induce barrier dysfunctions [ 16 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Blondel

Strazielle

Amara

et al. 2022

Fluids Barriers CNS

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Background Severe neonatal jaundice resulting from elevated levels of unconjugated bilirubin in the blood induces dramatic neurological impairment. Central oxidative stress and an inflammatory response have been associated with the pathophysiological mechanism. Cells forming the blood–brain barrier and the choroidal blood–CSF barrier are the first CNS cells exposed to increased plasma levels of unconjugated bilirubin. These barriers are key regulators of brain homeostasis and require active oxidative metabolism to fulfill their protective functions. The choroid plexus-CSF system is involved in neuroinflammatory processes. In this paper, we address the impact of neonatal hyperbilirubinemia on some aspects of brain barriers. We describe physiological changes in the neurovascular network, blood–brain/CSF barriers integrities, and CSF cytokine levels during the postnatal period in normobilirubinemic animals, and analyze these parameters in parallel in Gunn rats that are deficient in bilirubin catabolism and develop postnatal hyperbilirubinemia. Methods Gunn rats bearing a mutation in UGT1a genes were used. The neurovascular network was analyzed by immunofluorescence stereomicroscopy. The integrity of the barriers was evaluated by [14C]-sucrose permeability measurement. CSF cytokine levels were measured by multiplex immunoassay. The choroid plexus-CSF system response to an inflammatory challenge was assessed by enumerating CSF leukocytes. Results In normobilirubinemic animals, the neurovascular network expands postnatally and displays stage-specific regional variations in its complexity. Network expansion is not affected by hyperbilirubinemia. Permeability of the blood–brain and blood–CSF barriers to sucrose decreases between one- and 9-day-old animals, and does not differ between normobilirubinemic and hyperbilirubinemic rats. Cytokine profiles differ between CSF and plasma in all 1-, 9-, and 18-day-old animals. The CSF cytokine profile in 1-day-old animals is markedly different from that established in older animals. Hyperbilirubinemia perturbs these cytokine profiles only to a very limited extent, and reduces CSF immune cell infiltration triggered by systemic exposure to a bacterial lipopeptide. Conclusion The data highlight developmental specificities of the blood–brain barrier organization and of CSF cytokine content. They also indicate that a direct effect of bilirubin on the vascular system organization, brain barriers morphological integrity, and inflammatory response of the choroid plexus-CSF system is not involved in the alteration of brain functions induced by severe neonatal jaundice.

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Section: Introductionmentioning

confidence: 99%

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Blondel

Strazielle

Amara

et al. 2022

Fluids Barriers CNS

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“…It has been proven to inhibit neuronal arborization and to cause microglia and astrocytes to generate pro-inflammatory cytokines [8]. UCB causes neuron and glial cell destruction, as well as lesions in more vulnerable brain locations, potentially leading to permanent CNS dysfunction [33]. While glial cells are essential for maintaining brain networks, facilitating neuronal migration through development, and forming myelin, neurons are highly specialized for analyzing signals and communication (Fig.…”

Section: Cellular Mechanism Of Bilirubinmentioning

confidence: 99%

“…Additionally contributing to neuronal death, damage persistence, and inflammatory cytokine production is microglial phagocytosis [27]. Changes in brain homeostasis cause changes in microglia motility and morphology [33]. The interaction of UCB with microglia initially affects defensive processes involved with the expression nuclear factor kappa B (NF-B) and of mitogen-activated protein kinases (MAPKs) as well as enhanced phagocytosis and the subsequent generation of pro-inflammatory cytokines.…”

Section: Effect Of Bilirubin In Microgliamentioning

confidence: 99%

Bilirubin metabolism: delving into the cellular and molecular mechanisms to predict complications

Kumbhar,

Musale,

Jamsa

2024

Egypt J Intern Med

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Bilirubin is a metabolic product of heme, and an increase in its level may be toxic to the body. It may be conjugated or unconjugated. Encephalopathy is caused by unconjugated bilirubin has the ability to pass through the blood-brain barrier, entering the central nervous system. Conjugated forms of bilirubin result in biliary obstruction and a change in urine colour due to a decrease in excretion. Excessive hemolysis can result from hereditary and autoimmune diseases, deficient RBC membranes, enzyme deficiency, and hemoglobin structural anomalies. In this review, we summarize all the possible mechanisms and complications regarding bilirubin. Cellular and molecular functions and mechanisms of bilirubin are explained, followed by several complications viz neurotoxicity, auditory dysfunction, and nephrotoxicity. The cause of bilirubin-induced neuronal cell damage is likely due to the elevated levels of unconjugated bilirubin in plasma, mitochondrial, and endoplasmic reticulum (ER) membranes. These disruptions in the membranes could lead to harmful effects such as neuronal excitotoxicity, energy failure in mitochondria, or an increased concentration of calcium within the cells. At the cellular level, bilirubin exerts its toxic effect by disturbing the normal functioning of neuronal cells. Bilirubin's presence can cause certain inflammatory responses, resulting in the activation of proinflammatory cytokines. Additionally, research has demonstrated that bilirubin can negatively affect auditory abilities. It disrupts the integrity of auditory pathways, resulting in auditory dysfunction and potentially causing long-term hearing impairments in infants affected by it. In conclusion, a comprehensive understanding of the complications associated with unconjugated bilirubin in neonates is essential for improving clinical management and outcomes. Understanding the cellular and molecular pathophysiology of high bilirubin may lead to a new therapeutic approach.

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Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts

Kim,

Brustad,

Eliasen

et al. 2024

Med

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Bilirubin neurotoxicity: a narrative review on long lasting, insidious, and dangerous effects

Cited by 3 publications

References 203 publications

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Vascular network expansion, integrity of blood–brain interfaces, and cerebrospinal fluid cytokine concentration during postnatal development in the normal and jaundiced rat

Bilirubin metabolism: delving into the cellular and molecular mechanisms to predict complications

Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts

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