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Title: The activation of autophagy protects neurons and astrocytes against bilirubin-induced cytotoxicity
Authors: Qaisiya, Mohammed
Keywords: Cellular signaling
Bilirubin neurotoxicity
Issue Date: 20-Dec-2017
Publisher: ELSEVIER - Neuroscience Letter
Series/Report no.: 661:96-103;0.1016/j.neulet.2017.09.056
Abstract: Unconjugated bilirubin (UCB) neurotoxicity involves oxidative stress, calcium signaling and ER-stress. The same insults can also induce autophagy, a process of "self-eating", with both a pro-survival or a pro-apoptotic role. Our aim was to study the outcome of autophagy activation by UCB in the highly sensitive neuronal SH-SY5Y cells and in the resistant astrocytoma U87 cells. Upon treatment with a toxic dose of UCB, the conversion of LC3-I to LC3-II was detected in both cell lines. Inhibition of autophagy by E64d before UCB treatment increased SH-SY5Y cell mortality and made U87 cells sensitive to UCB. In SH-SY5Y autophagy related genes ATG8 (5 folds), ATG18 (5 folds), p62 (3 folds) and FAM 129A (4.5 folds) were induced 8h after UCB treatment while DDIT4 upregulation (13 folds) started at 4h. mTORC1 inactivation by UCB was confirmed by phosphorylation of 4EBP1. UCB induced LC3-II conversion was completely prevented by pretreating cells with the calcium chelator BAPTA and reduced by 65% using the ER-stress inhibitor 4-PBA. Pretreatment with the PKC inhibitor reduced LC3 mRNA by 70% as compared to cells exposed to UCB alone. Finally, autophagy induction by Trifluoroperazine (TFP) increased the cell viability of rat hippocampal primary neurons upon UCB treatment from 60% to 80%. In SH-SY5Y cells, TFP pretreatment blocked the UCB-induced cleaved caspase-3 protein expression, decreased LDH release from 50% to 23%, reduced the UCB-induction of HO1, CHOP and IL-8 mRNAs by 85%, 70% and 97%. Collectively these data indicate that the activation of autophagy protects neuronal cells from UCB cytotoxicity. The mechanisms of autophagy activation by UCB involves mTOR/ER-stress/PKC/calcium signaling.
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