Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor
Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor
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DOI：
10.1111/j.1471-4159.2011.07464.x
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发表时间：
2011-11-01
影响因子：
4.7
通讯作者：
Kiuchi, Kazutoshi
中科院分区：
文献类型：
--
作者：
Hirata, Yoko;Yamamoto, Hideko;Kiuchi, Kazutoshi
氯喹是一种广泛使用的抗疟疾和抗类风湿药物，据报道可诱导细胞凋亡和非凋亡性细胞死亡。越来越多的证据表明，氯喹可以使癌细胞对细胞死亡敏感，并通过抑制自噬来增加化疗诱导的细胞凋亡。然而，据报道，氯喹在低μ M浓度下诱导GM 1神经节苷脂在培养细胞中积累，并防止对小鼠血脑屏障的损伤。氯喹在低于其抑制溶酶体酶和自噬能力的浓度下是否具有神经保护特性仍然是未知的。在本研究中，我们证明，氯喹保护小鼠海马HT 22细胞从谷氨酸诱导的氧化应激，通过衰减产生过量的活性氧。拯救HT 22细胞免受氧化应激所需的氯喹浓度远低于足以诱导细胞死亡和抑制自噬的浓度。氯喹在低μ M浓度下增加了HT 22细胞中的GM 1水平，但谷氨酸诱导的细胞死亡发生在GM 1积累之前，这表明GM 1诱导与氯喹对谷氨酸诱导的细胞死亡的保护作用无关。有趣的是，BD 1047和NE-100，sigma-1受体拮抗剂，消除了氯喹对谷氨酸诱导的细胞死亡和活性氧产生的保护作用。此外，角皮美辛（SA 4503），一种sigma-1受体激动剂，防止谷氨酸诱导的细胞死亡和活性氧的产生。这些发现表明，氯喹在低于其抑制自噬和诱导细胞死亡的能力的浓度下能够通过减少活性氧通过σ-1受体的过度产生来拯救HT 22细胞免于谷氨酸诱导的细胞死亡。这些结果表明，潜在的使用氯喹，一个既定的抗疟疾剂，作为一种神经保护剂对氧化应激，这发生在各种神经退行性疾病。
Chloroquine, a widely used anti-malarial and anti-rheumatoid agent, has been reported to induce apoptotic and non-apoptotic cell death. Accumulating evidence now suggests that chloroquine can sensitize cancer cells to cell death and augment chemotherapy-induced apoptosis by inhibiting autophagy. However, chloroquine is reported to induce GM1 ganglioside accumulation in cultured cells at low mu M concentrations and prevent damage to the blood brain barrier in mice. It remains unknown whether chloroquine has neuroprotective properties at concentrations below its reported ability to inhibit lysosomal enzymes and autophagy. In the present study, we demonstrated that chloroquine protected mouse hippocampal HT22 cells from glutamate-induced oxidative stress by attenuating production of excess reactive oxygen species. The concentration of chloroquine required to rescue HT22 cells from oxidative stress was much lower than that sufficient enough to induce cell death and inhibit autophagy. Chloroquine increased GM1 level in HT22 cells at low mu M concentrations but glutamate-induced cell death occurred before GM1 accumulation, suggesting that GM1 induction is not related to the protective effect of chloroquine against glutamate-induced cell death. Interestingly, BD1047 and NE-100, sigma-1 receptor antagonists, abrogated the protective effect of chloroquine against glutamate-induced cell death and reactive oxygen species production. In addition, cutamesine (SA4503), a sigma-1 receptor agonist, prevented both glutamate-induced cell death and reactive oxygen species production. These findings indicate that chloroquine at concentrations below its ability to inhibit autophagy and induce cell death is able to rescue HT22 cells from glutamate-induced cell death by reducing excessive production of reactive oxygen species through sigma-1 receptors. These results suggest potential use of chloroquine, an established anti-malarial agent, as a neuroprotectant against oxidative stress, which occurs in a variety of neurodegenerative diseases.