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Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity.
Archives of Toxicology ( IF 6.1 ) Pub Date : 2020-03-03 , DOI: 10.1007/s00204-020-02659-9
Rossana Rauti 1, 2 , Mohammed Qaisiya 3, 4 , Claudio Tiribelli 3 , Laura Ballerini 1 , Cristina Bellarosa 3
Affiliation  

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.

中文翻译:

胆红素破坏新生儿海马神经元的钙稳态:一种新的神经毒性途径。

严重的高胆红素血症会导致新生儿胆红素脑病,引起不可逆的神经系统后遗症。我们调查了神经元对非结合胆红素(UCB)毒性的选择性脆弱性的性质。维持细胞内钙稳态对神经元存活至关重要。内质网(ER)应激期间钙从内质网释放可能导致通过Caspase-12激活的细胞凋亡。通过实时钙成像,我们监测了暴露于不断升高的UCB浓度的游离海马神经元和神经胶质细胞中钙信号的产生。我们展示了UCB改变细胞内钙稳态的能力,诱导了细胞内钙离子重复振荡的出现。还评估了细胞内钙存储的贡献以及与凋亡钙依赖性信号传导有关的蛋白质的诱导和活化。Thapsigargin是Sarco /内质网ATPase(SERCA)泵的特异抑制剂,可显着减少与UCB暴露相关的Ca2 +振荡的持续时间,这表明UCB强烈干扰了网状钙的储存。相反,在纯星形胶质细胞培养中,UCB不会改变自发的Ca2 +瞬时持续时间。与对照组相比,用UCB处理24小时的神经元细胞的GRP78,AT6,CHOP,钙蛋白酶和Caspase-12的蛋白质含量至少高两倍。当用ER应激抑制剂4-PBA预处理细胞时,UCB对钙依赖性钙蛋白酶和Caspase-12的诱导分别显着降低了50%和98%。
更新日期:2020-03-03
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