- MeSH
- antikonvulziva terapeutické užití MeSH
- bilirubin krev MeSH
- diferenciální diagnóza MeSH
- hemolytické anemie diagnóza etiologie MeSH
- hexokinasa * nedostatek MeSH
- kernikterus diagnóza etiologie MeSH
- krevní obraz MeSH
- lidé MeSH
- nemoci mozku etiologie MeSH
- novorozenec MeSH
- novorozenecká hyperbilirubinemie * etiologie komplikace terapie MeSH
- opožděná diagnóza škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- Publikační typ
- kazuistiky MeSH
Moderate neonatal jaundice is the most common clinical condition during newborn life. However, a combination of factors may result in acute hyperbilirubinemia, placing infants at risk of developing bilirubin encephalopathy and death by kernicterus. While most risk factors are known, the mechanisms acting to reduce susceptibility to bilirubin neurotoxicity remain unclear. The presence of modifier genes modulating the risk of developing bilirubin-induced brain damage is increasingly being recognised. The Abcb1 and Abcc1 members of the ABC family of transporters have been suggested to have an active role in exporting unconjugated bilirubin from the central nervous system into plasma. However, their role in reducing the risk of developing neurological damage and death during neonatal development is still unknown.To this end, we mated Abcb1a/b-/- and Abcc1-/- strains with Ugt1-/- mice, which develop severe neonatal hyperbilirubinemia. While about 60% of Ugt1-/- mice survived after temporary phototherapy, all Abcb1a/b-/-/Ugt1-/- mice died before postnatal day 21, showing higher cerebellar levels of unconjugated bilirubin. Interestingly, Abcc1 role appeared to be less important.In the cerebellum of Ugt1-/- mice, hyperbilirubinemia induced the expression of Car and Pxr nuclear receptors, known regulators of genes involved in the genotoxic response.We demonstrated a critical role of Abcb1 in protecting the cerebellum from bilirubin toxicity during neonatal development, the most clinically relevant phase for human babies, providing further understanding of the mechanisms regulating bilirubin neurotoxicity in vivo. Pharmacological treatments aimed to increase Abcb1 and Abcc1 expression, could represent a therapeutic option to reduce the risk of bilirubin neurotoxicity.
- MeSH
- bilirubin toxicita MeSH
- glukuronosyltransferasa fyziologie MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- mozeček účinky léků patologie MeSH
- myši knockoutované MeSH
- myši MeSH
- neurotoxické syndromy etiologie metabolismus patologie MeSH
- novorozená zvířata MeSH
- novorozenecká hyperbilirubinemie komplikace metabolismus patologie MeSH
- P-glykoprotein genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- viabilita buněk MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Severe hyperbilirubinemia is toxic during central nervous system development. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological damage and eventually death by kernicterus. Bilirubin neurotoxicity is characterized by a wide array of neurological deficits, including irreversible abnormalities in motor, sensitive and cognitive functions, due to bilirubin accumulation in the brain. Despite the abundant literature documenting the in vitro and in vivo toxic effects of bilirubin, it is unclear which molecular and cellular events actually characterize bilirubin-induced neurodegeneration in vivo. METHODS: We used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult. RESULTS: We showed that the exposure of developing cerebellum to sustained bilirubin levels induces the activation of oxidative stress, ER stress and inflammatory markers at the early stages of the disease onset. In particular, we identified TNFα and NFKβ as key mediators of bilirubin-induced inflammatory response. Moreover, we reported that M1 type microglia is increasingly activated during disease progression. Failure to counteract this overwhelming stress condition resulted in the induction of the apoptotic pathway and the generation of the glial scar. Finally, bilirubin induced the autophagy pathway in the stages preceding death of the animals. CONCLUSIONS: This study demonstrates that inflammation is a key contributor to bilirubin damage that cooperates with ER stress in the onset of neurotoxicity. Pharmacological modulation of the inflammatory pathway may be a potential intervention target to ameliorate neonatal lethality in Ugt1-/-mice.
- MeSH
- degenerace nervu etiologie metabolismus patologie MeSH
- glukuronosyltransferasa nedostatek MeSH
- modely nemocí na zvířatech MeSH
- mozeček patologie MeSH
- myši knockoutované MeSH
- myši MeSH
- novorozená zvířata MeSH
- novorozenecká hyperbilirubinemie komplikace patologie MeSH
- zánět etiologie metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Therapies to prevent severe neonatal unconjugated hyperbilirubinemia and kernicterus are phototherapy and, in unresponsive cases, exchange transfusion, which has significant morbidity and mortality risks. Neurotoxicity is caused by the fraction of unconjugated bilirubin not bound to albumin (free bilirubin, Bf). Human serum albumin (HSA) administration was suggested to increase plasma bilirubin-binding capacity. However, its clinical use is infrequent due to difficulties to address its potential preventive and curative benefits, and to the absence of reliable markers to monitor bilirubin neurotoxicity risk. We used a genetic mouse model of unconjugated hyperbilirubinemia showing severe neurological impairment and neonatal lethality. We treated mutant pups with repeated HSA administration since birth, without phototherapy application. Daily intraperitoneal HSA administration completely rescued neurological damage and lethality, depending on dosage and administration frequency. Albumin infusion increased plasma bilirubin-binding capacity, mobilizing bilirubin from tissues to plasma. This resulted in reduced plasma Bf, forebrain and cerebellum bilirubin levels. We showed that, in our experimental model, Bf is the best marker to determine the risk of developing neurological damage. These results support the potential use of albumin administration in severe acute hyperbilirubinemia conditions to prevent or treat bilirubin neurotoxicity in situations in which exchange transfusion may be required.
- MeSH
- bilirubin krev MeSH
- fototerapie metody MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mozeček účinky léků MeSH
- myši MeSH
- nemoci nervového systému etiologie prevence a kontrola MeSH
- novorozenecká hyperbilirubinemie krev komplikace MeSH
- novorozenecká žloutenka krev komplikace MeSH
- sérový albumin aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Unconjugated bilirubin (UCB), the principal mammalian bile pigment, is the end product of heme catabolism. Both belong to the superfamily of tetrapyrrolic compounds that serve multiple biological functions in animals and plants. Its six internal hydrogen bonds give UCB a unique structure responsible for its physico-chemical properties and biological effects. Like many weakly-polar, poorly-soluble compounds, UCB is transported in blood tightly bound to albumin, with less than 0.01% of total bilirubin circulating in an unbound form (free bilirubin, Bf). This fraction governs the diffusion of UCB into tissues, and therefore Bf is responsible for both its beneficial and toxic effects on cells. Although, UCB was long thought to be a non-functional waste product, recent studies have shown that the antioxidant effects of mildly elevated serum bilirubin levels, as well as activation of heme oxygenase, may protect against diseases associated with oxidative stress, such as atherosclerosis. By contrast, markedly elevated serum UCB levels may cause severe neurological damage, especially in neonates. The regulation of cellular UCB content, by its conjugation, oxidation, and export, are, therefore of paramount importance to cellular health.
- MeSH
- bilirubin chemie krev metabolismus MeSH
- biologický transport MeSH
- hem metabolismus MeSH
- hyperbilirubinemie komplikace metabolismus MeSH
- játra metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- nemoci centrálního nervového systému etiologie metabolismus MeSH
- novorozenec MeSH
- novorozenecká hyperbilirubinemie komplikace metabolismus MeSH
- oxidace-redukce MeSH
- oxidační stres MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- fototerapie metody normy využití MeSH
- imunoterapie metody normy MeSH
- klinické laboratorní techniky metody využití MeSH
- krevní transfuze metody normy MeSH
- lidé MeSH
- neonatologie metody normy MeSH
- novorozenec MeSH
- novorozenecká hyperbilirubinemie klasifikace komplikace terapie MeSH
- ošetřovatelství novorozenců metody normy MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH