Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress-Induced Cell Damage: an Involvement of Cathepsin D Inhibition
Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress-Induced Cell Damage: an Involvement of Cathepsin D Inhibition
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DOI：
10.1007/s12640-020-00164-6
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发表时间：
2020-03-01
影响因子：
3.7
通讯作者：
Lason, Wladyslaw
中科院分区：
文献类型：
--
作者：
Jantas, Danuta;Chwastek, Jakub;Lason, Wladyslaw
坏死性上睑下垂是最近发现的一种非凋亡性程序性细胞死亡形式，可涉及许多病理条件，包括神经元细胞死亡。此外，在体外和体内脑缺血模型中，坏死他汀-1 （nec1）对这一过程的抑制已被证明具有神经保护作用。然而，这种类型的细胞死亡在氧化应激诱导的神经元细胞损伤中所涉及的认识较少。因此，我们在过氧化氢（H2O2）诱导的人神经母细胞瘤SH-SY5Y和小鼠海马HT-22细胞系细胞损伤模型中测试了Nec-1（一种坏死性凋亡抑制剂）的作用。结果表明，Nec-1 （10-40 μ M）对未分化（UN-）和神经元分化（RA-） SH-SY5Y细胞H2O2诱导的细胞死亡有较强的抑制作用。此外，Nec-1部分减轻了6-羟多巴胺对UN-和RA-SH-SY5Y细胞的损伤。Nec-1在两种细胞表型中的保护作用与caspase-3抑制剂的作用相似，并且在联合治疗后这种作用没有增强。此外，非特异性凋亡和坏死抑制剂姜黄素增强了Nec-1对h2o2引起的细胞损伤的有益作用，尽管仅在RA-SH-SY5Y细胞中。接下来，我们发现c-1对h2o2诱导的SH-SY5Y细胞损伤的神经保护作用机制涉及抑制溶酶体蛋白酶、组织蛋白酶D，而不是抑制caspase-3或calpain活性。在HT-22细胞中，Nec-1对两种氧化应激模型（H2O2和谷氨酸）具有保护作用，这种作用被caspase抑制剂阻断。我们的数据显示，坏死性下垂抑制剂Nec-1对氧化应激诱导的细胞损伤具有神经保护作用，并指出其作用机制涉及组织蛋白酶D的抑制。此外，坏死下垂和细胞凋亡之间的细胞类型特异性相互作用已被证实。
Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H2O2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 mu M) attenuated the cell death induced by H2O2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN- and RA-SH-SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H2O2-evoked cell damage albeit only in RA-SH-SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H2O2-induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H2O2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.