中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1099-1106.doi: 10.4103/1673-5374.355815

• 原著:退行性病与再生 • 上一篇    下一篇

胰岛素样生长因子 2 对6-羟多巴胺诱导帕金森病小鼠模型的神经保护作用

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    中国国家自然科学基金项目(81873742,81901195),南通科技项目(JC2020052,JCZ19087)

Neuroprotective effects of insulin-like growth factor-2 in 6-hydroxydopamine-induced cellular and mouse models of Parkinson’s disease

Hai-Ying Zhang1, 2, #, Yong-Cheng Jiang1, 2, #, Jun-Rui Li3, Jia-Nan Yan1, 2, Xin-Jue Wang1, 2, Jia-Bing Shen1, 2, Kai-Fu Ke1, *, Xiao-Su Gu1, *   

  1. 1Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China;  2Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China;  3Department of Clinical Medicine, The First Clinical Medical College of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Xiao-Su Gu, MD, Guxiaosu001@163.com; Kai-Fu Ke, MD, kekaifu_nt@126.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81873742 (to KFK), 81901195 (to JBS), and Nantong Technology Project, Nos. JC2020052 (to XSG), JCZ19087 (to XSG).

摘要:

作者团队既往研究发现,皮肤前体细胞源性许旺细胞可对中枢神经系统起保护作用,并以蛋白质组学分析推测其保护作用可能归因于释放胰岛素样生长因子2为宿主细胞提供营养支持。因此此次实验首先以6-羟基多巴胺诱导建立了帕金森病细胞模型,并以皮肤前体细胞源性许旺细胞的条件培养基进行预处理,发现SH-SY5Y细胞活性得到显著改善,而加入胰岛素样生长因子2中和抗体后,其保护作用明显减弱。继而检测了帕金森病患者及小鼠模型外周血血清,发现其中胰岛素样生长因子2水平均明显增加。然后以胰岛素样生长因子2预处理帕金森病细胞模型或胰岛素样生长因子2鼻内给药治疗6-羟基多巴胺诱导的帕金森病小鼠模型,发现多巴胺神经元标志物酪氨酸羟化酶水平明显恢复,且α-突触核蛋白聚集减少,同时可胰岛素样生长因子2受体下调缓解。最后在体外实验中发现胰岛素样生长因子2还可激活帕金森病细胞模型中的肌酸肌醇3激酶/AKT信号通路。上述结果提示皮肤前体细胞源性许旺细胞对中枢神经系统的保护作用是通过胰岛素样生长因子2实现的,且胰岛素样生长因子2可能通过胰岛素样生长因子2受体/肌酸肌醇3激酶/AKT通路发挥神经保护作用,因此胰岛素样生长因子2可能是治疗帕金森病的一个有趣候选靶点。

https://orcid.org/0000-0002-3064-956X (Xiao-Su Gu)

关键词: 胰岛素样生长因子2, 皮肤前体细胞源性许旺细胞, 胰岛素样生长因子2受体, 6-羟多巴胺, α-突触核蛋白, 神经保护, 帕金森病, 神经退行

Abstract: Skin-derived precursor Schwann cells have been reported to play a protective role in the central nervous system. The neuroprotective effects of skin-derived precursor Schwann cells may be attributable to the release of growth factors that nourish host cells. In this study, we first established a cellular model of Parkinson’s disease using 6-hydroxydopamine. When SH-SY5Y cells were pretreated with conditioned medium from skin-derived precursor Schwann cells, their activity was greatly increased. The addition of insulin-like growth factor-2 neutralizing antibody markedly attenuated the neuroprotective effects of skin-derived precursor Schwann cells. We also found that insulin-like growth factor-2 levels in the peripheral blood were greatly increased in patients with Parkinson’s disease and in a mouse model of Parkinson’s disease. Next, we pretreated cell models of Parkinson’s disease with insulin-like growth factor-2 and administered insulin-like growth factor-2 intranasally to a mouse model of Parkinson’s disease induced by 6-hydroxydopamine and found that the level of tyrosine hydroxylase, a marker of dopamine neurons, was markedly restored, α-synuclein aggregation decreased, and insulin-like growth factor-2 receptor down-regulation was alleviated. Finally, in vitro experiments showed that insulin-like growth factor-2 activated the phosphatidylinositol 3 kinase (PI3K)/AKT pathway. These findings suggest that the neuroprotective effects of skin-derived precursor Schwann cells on the central nervous system were achieved through insulin-like growth factor-2, and that insulin-like growth factor-2 may play a neuroprotective role through the insulin-like growth factor-2 receptor/PI3K/AKT pathway. Therefore, insulin-like growth factor-2 may be an useful target for Parkinson’s disease treatment.

Key words: 6-hydroxydopamine, alpha-synuclein, insulin-like growth factor-2 receptor, insulin-like growth factor-2, neurodegeneration, neuroprotection, Parkinson’s disease, skin-derived precursor Schwann cells