Astrocytic Insulin-Like Growth Factor-1 Protects Neurons Against Excitotoxicity
Astrocytic Insulin-Like Growth Factor-1 Protects Neurons Against Excitotoxicity
复制标题
星形胶质细胞胰岛素样生长因子 1 保护神经元免受兴奋性毒性
DOI：
10.3389/fncel.2019.00298
复制
发表时间：
2019-07-09
影响因子：
5.3
通讯作者：
Zheng, Ping
中科院分区：
文献类型：
--
作者：
Chen, Wei;He, Bin;Zheng, Ping
背景外源性胰岛素样生长因子-1（IGF-1）在脑损伤动物模型中具有神经保护作用，但也可引起啮齿类动物的过度兴奋。在这方面，内源性IGF-1在脑损伤（如兴奋性毒性，脑损伤中的常见病理学）的脑反应中的作用仍有待阐明。在这里，我们研究了细胞特异性内源性IGF-1在红藻氨酸（KA）诱导的神经元变性中的潜在作用。方法原代培养的皮层神经元给予红藻氨酸，加入共培养的星形胶质细胞作为支持系统。检测各组细胞增殖率、IGF-1水平，并应用PCR-Chip技术检测IGF-1下游基因。此外，我们将星形胶质细胞IGF-1的病毒转移应用于用KA治疗的啮齿动物，并评估了这些啮齿动物中相关的分子标志物和行为结果。结果KA可诱导神经元细胞死亡和tau蛋白过度磷酸化;共培养的星形胶质细胞可预防这些病理变化，而用IGF-1 R抑制剂AG 1024阻断星形胶质细胞IGF-1可消除这种拯救作用。PCR-Chip分析证实星形胶质细胞IGF-1可降低KA处理的神经元中Tyr 216处的p-GSK-3，并且这种作用也被AG 1024消除。此外，体内研究表明，星形胶质细胞IGF-1的基因转移减少KA小鼠中的p-tau和认知功能障碍。结论星形胶质细胞IGF-1在中枢神经系统退行性变过程中具有神经保护作用。
Background Exogenous insulin like growth factor-1 (IGF-1) is known to be neuroprotective in animal models with brain insults, while it can also cause hyperexcitability in rodents. In this regard, the role of endogenous IGF-1 in brain responses to brain insults like excitotoxicity, a common pathology in brain injuries, remains to be elucidated. Here, we investigated the potential role of cell-specific endogenous IGF-1 in the kainic acid (KA) -induced degeneration of the neurons. Methods Kainic acid was given to primary cultured cortical neurons and co-cultured astrocytes were added as a supportive system. We evaluated the cell proliferation rate, IGF-1 level in different groups and applied the PCR-Chip assay to explore the downstream of IGF-1. In addition, we applied the viral transfer of astrocytic IGF-1 to rodents treated with KA and assessed the associated molecular marker and behavioral outcomes in these rodents. Results We found KA induced increased cell death and hyperphosphorylated tau in neurons; co-cultured astrocytes could prevent these pathologies, and this rescuing effect was abrogated with blockade of the astrocytic IGF-1 with AG1024 (IGF-1R inhibitor). PCR-Chip assay identified that astrocytic IGF-1 could decrease the p-GSK-3 at Tyr 216 in neurons treated with KA and this effect was abrogated with AG1024 as well. In addition, in vivo study showed that gene transfer of astrocytic IGF-1 decreased p-tau and cognitive dysfunction in KA mice. Conclusion Our results show astrocytic IGF-1 exhibits neuroprotective properties in neurodegenerative processes in the CNS.