Influence of hypoxia and ischemia preconditioning on bilirubin damage to astrocytes

Falcão, Ana S.; Silva, Rui F. M.; Fernandes, Adelaide; Brito, Maria Alexandra; Brites, Dora

doi:10.1016/j.brainres.2007.02.039

Cited by 22 publications

(14 citation statements)

References 68 publications

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“…Bilirubin at high concentrations (>300 μM, or 25 mg/100 ml plasma level) has been long considered as a cytotoxic factor that deposits in the brain and causes encephalopathy in severely jaundiced newborn babies [143]. High concentrations of bilirubin (>50 μM) are cytotoxic and cause neuronal and glial cell death by apoptosis and necrosis [144,145]. However, cerebral vascular endothelial cells are resistant to bilirubin cytotoxicity: 3h-exposure to 50μM unconjugated bilirubin does not cause apoptosis (Parfenova, unpublished observations).…”

Section: A Anti-oxidant and Anti-apoptotic Properties Of Bilirubinmentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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Section: A Anti-oxidant and Anti-apoptotic Properties Of Bilirubinmentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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“…Indeed, severe postnatal hypoxia has been reported to significantly increase bilirubin brain levels in newborn rats [33], with preferential bilirubin accumulation in cerebral areas corresponding to those more severely injured as a result of perinatal asphyxia [34]. At the cellular level, it has been reported that susceptibility of developing neurons to bilirubin damage is enhanced by associated hypoxia [35], whereas astroglial bilirubin damage is aggravated upon concomitant hypoxia and combined oxygeneglucose deprivation followed by re-oxygenation [36]. Most attractively, a recent case report of a preterm infant with acute kernicterus, where features such as axon and myelin loss were observed, showed signs of hypoxia and suspected sepsis [37], suggesting that the mix of these neonatal conditions may contribute to an aggravated myelin impairment in hyperbilirubinemic infants.…”

Section: Introductionmentioning

confidence: 99%

Bilirubin-induced neural impairment: A special focus on myelination, age-related windows of susceptibility and associated co-morbidities

Brites

Fernandes

2015

Seminars in Fetal and Neonatal Medicine

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“…Further risk factors beyond prematurity include acidosis, sepsis, hypothermia, hematological/genetic abnormalities intraventricular hemorrhage, use of drugs that bind to albumin, and hypoxia [19]. Hypoxia may have additive toxic effects in combination with hyperbilirubinemia, as hypoxia before or at the time of elevated TB has been demonstrated to increase glial cell apoptosis and necrosis [20]. Acidosis may contribute to increased toxicity of bilirubin due to increased cerebral blood flow, and acid–base changes in the bilirubin molecule allowing it to be partially polar [21].…”

Section: Severity Of Hyperbilirubinemiamentioning

confidence: 99%

Movement disorders due to bilirubin toxicity

Rose

Vassar

2015

Seminars in Fetal and Neonatal Medicine

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Summary Advances in the care of neonatal hyperbilirubinemia have decreased the incidence of kernicterus. However, neonatal exposure to high levels of bilirubin continues to cause severe motor symptoms and cerebral palsy (CP). Exposure to moderate levels of unconjugated bilirubin may also cause damage to the developing central nervous system, specifically the basal ganglia and cerebellum. Brain lesions identified using magnetic resonance imaging following extreme hyperbilirubinemia have been linked to dyskinetic CP. Newer imaging techniques, such as diffusion tensor imaging or single-photon emission computed tomography, allow quantification of more subtle white matter injury following presumed exposure to unbound bilirubin, and may explain more subtle movement disorders. New categories of bilirubin-induced neurologic dysfunction, either independently or characterized by subtle bilirubin encephalopathy, following moderate hyperbilirubinemia have been implicated in long-term motor function. Further research is needed to identify subtle impairments resulting from moderate to severe neonatal hyperbilirubinemia, understand the influence of perinatal risk factors on bilirubin toxicity, and develop neuroprotective treatment strategies to prevent movement disorders due to bilirubin toxicity.

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Influence of hypoxia and ischemia preconditioning on bilirubin damage to astrocytes

Cited by 22 publications

References 68 publications

Cerebroprotective Functions of HO-2

Cerebroprotective Functions of HO-2

Bilirubin-induced neural impairment: A special focus on myelination, age-related windows of susceptibility and associated co-morbidities

Movement disorders due to bilirubin toxicity

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