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Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity

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dc.contributor.author Rauti, Rossana
dc.contributor.author Qaisiya, Mohammed
dc.contributor.author Tiribelli, Claudio
dc.contributor.author Ballerini, Laura
dc.contributor.author Bellarosa, Cristina
dc.date.accessioned 2022-03-01T09:30:06Z
dc.date.available 2022-03-01T09:30:06Z
dc.date.issued 2020-03-03
dc.identifier.uri http://dspace.hebron.edu:80/xmlui/handle/123456789/1107
dc.description.abstract Severe hyperbilirubinemia leads to bilirubin encephalopathy in neonates, causing irreversible neurological sequelae. We investigated the nature of neuronal selective vulnerability to unconjugated bilirubin (UCB) toxicity. The maintenance of intracellular calcium homeostasis is crucial for neuron survival. Calcium release from endoplasmic reticulum (ER) during ER-stress can lead to apoptosis trough the activation of Caspase-12. By live calcium imaging we monitored the generation of calcium signals in dissociated hippocampal neurons and glial cells exposed to increasing UCB concentrations. We showed the ability of UCB to alter intracellular calcium homeostasis, inducing the appearance of repetitive intracellular calcium oscillations. The contribution of intracellular calcium stores and the induction and activation of proteins involved in the apoptotic calcium-dependent signaling were also assessed. Thapsigargin, a specific inhibitor of Sarco/endoplasmic reticulum ATPase (SERCA) pumps, significantly reduced the duration of Ca2+ oscillation associated with UCB exposure indicating that UCB strongly interfered with the reticulum calcium stores. On the contrary, in pure astrocyte cultures, spontaneous Ca2+ transient duration was not altered by UCB. The protein content of GRP78, AT6, CHOP, Calpain and Caspase-12 of neuronal cells treated with UCB for 24 h was at least twofold higher compared to controls. Calcium-dependent Calpain and Caspase-12 induction by UCB were significantly reduced by 50% and 98%, respectively when cells were pretreated with the ER-stress inhibitor 4-PBA. These results show the strong and direct interference of UCB with neuronal intracellular Ca2+ dynamics, suggesting ER Ca2+ stores as a primary target of UCB toxicity with the activation of the apoptotic ER-stress-dependent pathway. en_US
dc.language.iso en en_US
dc.publisher Springerlink en_US
dc.subject Apoptotic pathways; Bilirubin neurotoxicity; Calcium imaging; ER Ca2+ stores; Kernicterus; Neuroscience. en_US
dc.title Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity en_US
dc.type Article en_US

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