GLUCAGON-LIKE PEPTIDE-1 (GLP-1) PROTECTS AGAINST METHYLGLYOXAL-INDUCED PC12 CELL APOPTOSIS THROUGH THE PI3K/Akt/mTOR/GCLc/REDOX SIGNALING PATHWAY
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) PROTECTS AGAINST METHYLGLYOXAL-INDUCED PC12 CELL APOPTOSIS THROUGH THE PI3K/Akt/mTOR/GCLc/REDOX SIGNALING PATHWAY
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DOI：
10.1016/j.neuroscience.2009.05.025
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发表时间：
2009-09-15
期刊：
影响因子：
3.3
通讯作者：
Joh, T.
中科院分区：
文献类型：
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作者：
Kimura, R.;Okouchi, M.;Joh, T.
患有长期糖尿病的患者通常会发展为糖尿病脑病，其特征在于认知障碍和痴呆。氧化应激诱导的神经细胞凋亡是一个促成因素。胰高血糖素样肽（GLP）-1最近已成为糖尿病患者的一种有吸引力的治疗方式。它也很容易进入大脑，防止神经细胞凋亡，并改善阿尔茨海默病的认知障碍特征。因此，我们研究了GLP-1是否可以防止氧化应激诱导的嗜铬细胞瘤（PC 12）细胞的神经细胞凋亡。将PC 12细胞暴露于1 mM甲基乙二醛（MG）或MG加3.30 μ g/ml GLP-1。然后测定细胞凋亡、磷脂酰肌醇-3激酶/Akt/雷帕霉素哺乳动物靶点/γ-谷氨酰半胱氨酸连接酶催化亚基（GCLc）的表达和磷酸化以及氧化还原平衡。结果表明，MG诱导PC 12细胞凋亡与氧化还原（谷胱甘肽（GSH）和GSH/谷胱甘肽二硫化物[GSSG]）失衡有关。GLP-1可防止MG诱导的细胞凋亡，这对应于PI 3 K、Akt和mTOR的磷酸化，以及GCLc的上调和氧化还原失衡的恢复。PI 3 K（LY 294002）、Akt（Akt-I）和mTOR（雷帕霉素）抑制剂可降低GLP-1诱导的GCLc上调及其对MG诱导的PC 12凋亡的保护作用。GLP-1诱导的氧化还原恢复也被雷帕霉素减弱。总之，GLP-1的神经保护作用是由于PI 3 K/Akt/mTOR/GCLc/氧化还原信号传导的增强。(C)2009年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Patients with long-standing diabetes commonly develop diabetic encephalopathy, which is characterized by cognitive impairment and dementia. Oxidative stress-induced neuronal cell apoptosis is a contributing factor. Glucagon-like peptide (GLP)-1 has recently become an attractive treatment modality for patients with diabetes. It also readily enters the brain, prevents neuronal cell apoptosis, and improves the cognitive impairment characteristic of Alzheimer's disease. Therefore, we investigated whether GLP-1 could protect against oxidative stress-induced neuronal cell apoptosis in pheochromocytoma (PC12) cells. PC12 cells were exposed to 1 mM methylglyoxal (MG) or MG plus 3.30 mu g/ml GLP-1. Cell apoptosis, expression and phosphorylation of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/gamma-glutamylcysteine ligase catalytic subunit (GCLc), and redox balance were then determined. The data showed that MG induced PC12 apoptosis in accordance with the redox (glutathione (GSH) and GSH/glutathione disulfide [GSSG]) imbalance. GLP-1 protected against this MG-induced apoptosis, which corresponded to the phosphorylation of PI3K, Akt, and mTOR, as well as the upregulation of GCLc and the restoration of the redox imbalance. Inhibitors of PI3K (LY294002), Akt (Akt-I), and mTOR (rapamycin) reduced the GLP-1-induced GCLc upregulation and its protection against MG-induced PC12 apoptosis. The GLP-1-induced redox restoration was also attenuated by rapamycin. In conclusion, the neuroprotective effect of GLP-1 is due to an enhancement of PI3K/Akt/mTOR/GCLc/redox signaling. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.