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Monitoring Astrocyte Reactivity and Proliferation in Vitro Under Ischemic-Like Conditions
Published on: October 21, 2017
Influence of hypoxia and ischemia preconditioning on bilirubin damage to astrocytes
Ana S Falcão1, Rui F M Silva, Adelaide Fernandes
1Centro de Patogénese Molecular-UBMBE, Faculdade de Farmácia, University of Lisbon, Av. Forças Armadas, 1600-083 Lisboa, Portugal.
Insights
Perinatal hypoxia-ischemia increases glial cell vulnerability to bilirubin-induced brain damage. This preconditioning enhances cell death and inflammation, raising the risk of encephalopathy in newborns.
Area of Science:
- Neuroscience
- Neonatal Medicine
- Cellular Biology
Background:
- Perinatal hypoxia-ischemia is a leading cause of childhood neurologic disability and neonatal mortality.
- Neonatal hyperbilirubinemia, characterized by high unconjugated bilirubin (UCB) levels, can cause brain damage (encephalopathy).
- Hypoxia-ischemia may increase susceptibility to UCB encephalopathy, but underlying cellular mechanisms are unclear.
Purpose of the Study:
- To investigate if hypoxia (HP) or oxygen-glucose deprivation (OGD) followed by reoxygenation affects glial cell susceptibility to UCB injury.
- To elucidate cellular mechanisms linking perinatal insults to increased UCB neurotoxicity.
Main Methods:
- Cultured astrocytes were subjected to 4 hours of HP or OGD.
- Cells were reoxygenated for 12 hours before a 4-hour incubation with UCB.
- UCB toxicity under preconditioned conditions was compared to normoxic controls.
Main Results:
- HP and OGD preconditioning significantly increased glial cell vulnerability to UCB.
- Preconditioning enhanced UCB-induced cell death via apoptosis and necrosis.
- Preconditioning augmented UCB-stimulated inflammatory responses, involving nuclear factor kappaB activation.
Conclusions:
- Hypoxia and oxygen-glucose deprivation enhance glial cell susceptibility to bilirubin neurotoxicity.
- These findings reveal a cellular basis for increased brain damage risk in jaundiced newborns with perinatal hypoxic-ischemic events.
- This study highlights the critical role of glial cell responses in mediating UCB encephalopathy under adverse perinatal conditions.
Abstract:
Hypoxia-ischemia in the perinatal period is a common cause of neurologic disability in children and is often associated with neonatal morbidity and mortality. Another frequent condition of the newborn is hyperbilirubinemia and it is well known that deposition of unconjugated bilirubin (UCB) in the central nervous system can damage nerve cells and cause encephalopathy. Interestingly, some studies report the onset of cerebral hypoxia-ischemia as a risk factor for UCB encephalopathy, since that condition often precedes neonatal hyperbilirubinemia. However, the cellular mechanisms triggered by hypoxia-ischemia that may enforce UCB deleterious effects are not well elucidated. Therefore, we designed this study to investigate whether hypoxia (HP) or combined oxygen-glucose deprivation (OGD) followed by reoxygenation, modifies glial cell susceptibility to UCB injury. Thus, cultured astrocytes were exposed to HP or OGD for 4 h and returned to normoxic conditions for another 12 h prior to incubation with UCB for 4 h. HP and OGD effects in UCB toxicity were compared to normoxic conditions. Our results demonstrate that HP and OGD preconditioning increase the vulnerability of glial cells to UCB damage by enhancing some of the deleterious effects of UCB, namely cell death by both apoptosis and necrosis. This preconditioning also augments the UCB-induced stimulation of an inflammatory response by an effect that involves the activation of the nuclear factor kappaB activation. These findings provide a novel basis for the increased risk of brain damage in jaundiced newborns that were previously exposed to hypoxia or ischemia during the perinatal period, namely during delivery.
