Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups

Daood, Monica J.; Hoyson, Mitchell; Watchko, Jon F.

doi:10.1038/pr.2012.111

Cited by 27 publications

(23 citation statements)

References 37 publications

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“…All these events activate the mitochondrial apoptotic pathway [43] leading to increased oxidative stress and cellular redox status imbalance [44, 45]. Likewise, others and we showed that oxidative stress is a key feature of neurotoxicity animal models of systemic hyperbilirubinemia [18, 26, 46]. However, oxidative stress response to bilirubin did not elicit the induction of Cyps in our mouse model (Additional file 7B), differently to what observed in the Gunn rat [47], an animal model of the disease presenting a milder phenotype.…”

Section: Discussionmentioning

confidence: 96%

“…The concept that several components participate in the response to bilirubin neurotoxicity is supported by the observation that the treatment with antioxidants of Gunn rats having sulfadimethoxine-induced encephalopathy was not sufficient to reduce BIND. On the contrary, minocycline, a molecule with multiple properties in addition to the antioxidant effect, was able to prevent BIND [46]. It remains to be tested if the use of these compounds will ameliorate neurodegeneration and increase survival of the lethal mouse model presented in this study.…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

Vodret

Bortolussi

Jašprová

et al. 2017

J Neuroinflammation

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BackgroundSevere 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. MethodsWe used a mouse model of neonatal hyperbilirubinemia to temporally and spatially define the response of the developing cerebellum to the bilirubin insult.ResultsWe 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0838-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

Vodret

Bortolussi

Jašprová

et al. 2017

J Neuroinflammation

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“…Indeed, Lertvorachon et al [20] reacted tetracyclines with hydrazine to create 1,12-substituted tetracyclines. One of these “pentacyclines”, 12 S -hydroxy-1,12-pyrazolinominocycline (PMIN), is a potent antioxidant [8, 20], which neither inhibits the growth of Escherichia coli or Staphylococcus aureus nor chelates Ca 2+ [2, 20]. Despite this profile, PMIN reduces formalin-induced licking behavior and carrageenan-induced edema in mice, and these effects are comparable to those of minocycline [2].…”

Section: Introductionmentioning

confidence: 99%

A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

Bastos¹,

Godin²,

Zhang³

et al. 2013

Neuroscience Letters

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Many studies have shown that minocycline, an antibacterial tetracycline, suppresses experimental pain. While minocycline’s positive effects on pain resolution suggest that clinical use of such drugs may prove beneficial, minocycline’s antibiotic actions and divalent cation (Ca2+; Mg2+) chelating effects detract from its potential utility. Thus, we tested the antiallodynic effect induced by a non-antibacterial, non-chelating minocycline derivative in a model of neuropathic pain and performed an initial investigation of its anti-inflammatory effects in vitro. Intraperitoneal minocycline (100 mg/kg) and 12S-hydroxy-1,12-pyrazolinominocycline (PMIN; 23.75, 47.50 or 95.00 mg/kg) reduce the mechanical allodynia induced by chronic constriction injury of mouse sciatic nerve. PMIN reduces the LPS-induced production of PGE2 by primary microglial cell cultures. Human embryonic kidney cells were transfected to express human toll-like receptors 2 and 4, and the signaling via both receptors stimulated with PAM3CSK4 or LPS (respectively) was affected either by minocycline or PMIN. Importantly, these treatments did not affect the cell viability, as assessed by MTT test. Altogether, these results reinforce the evidence that the anti-inflammatory and experimental pain suppressive effects induced by tetracyclines are neither necessarily linked to antibacterial nor to Ca2+ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the management of neuropathic pain, as its lack of antibacterial and Ca2+ chelating activities might confer greater safety over conventional tetracyclines.

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“…The former is used as an experimental model of dystonia [33,62,63]. Although these models show basal ganglia injury [4,65], the sine qua non of bilirubin-induced murine neuropathology is cerebellar damage [4,65] and resultant cerebellar hypoplasia [21,29,66]. We speculate that this cerebellar injury is a contributor to the motor network disruption involved in the pathophysiology of bilirubin-induced dystonia.…”

Section: Cerebellar Projectionsmentioning

confidence: 96%

“…ABE does not occur spontaneously in Gunn rat pups of the current era, but must be induced by the administration of: (i) sulfadimethoxine to displace bilirubin from albumin [21,28,29], or (ii) phenylhydrazine to produce hemolysis [30]. These conditions result in markedly elevated CNS bilirubin levels [31,32] and overt signs of advanced bilirubin encephalopathy including severe neuromotor abnormalities [29,33] and abnormal ABER [28,30,34]. A small percentage of Gunn rat pups will die due to the hazardously high CNS bilirubin levels during induced ABE.…”

Section: Cerebellar Vulnerability To Bilirubin-induced Injurymentioning

confidence: 99%

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

Watchko

Painter

Panigrahy

2015

Seminars in Fetal and Neonatal Medicine

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Lipid peroxidation is not the primary mechanism of bilirubin-induced neurologic dysfunction in jaundiced Gunn rat pups

Cited by 27 publications

References 37 publications

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

Are the neuromotor disabilities of bilirubin-induced neurologic dysfunction disorders related to the cerebellum and its connections?

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