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Insulin attenuates epileptiform discharge-induced oxidative stress by increasing zinc-α2-glycoprotein in primary cultured cortical neurons

Wei, Xin*; Liu, Xi*; Tan, Changhong; Mo, Lijuan; Wang, Hui; Peng, Wuxue; Zhou, Wen; Jiang, Jin; Deng, Fen; Chen, Lifen

doi: 10.1097/WNR.0000000000001250

Zinc-α2-glycoprotein (ZAG) is decreased in neurons of epilepsy patients and models. Either insulin or overexpressing ZAG suppresses seizure and epileptiform discharges. ZAG is known to influence insulin sensitivity of tissues, but whether insulin regulates ZAG is unknown. This study investigated the effect and mechanism of insulin on ZAG expression and epileptiform discharge-induced oxidative stress. Primary cultured cortical neurons were treated with insulin, AXL1717 (inhibitor of insulin-like growth factor-1 receptor), or BMS-754807 (inhibitor of both insulin receptor and insulin-like growth factor-1 receptor). Mg2+-free epileptiform discharge model was also made. Levels of ZAG and AZGP1 mRNAs in neurons were measured. Oxidative stress in Mg2+-free-treated treated neurons underwent AZGP1 knock-down, AZGP1 overexpression, or insulin treatment was determined. Insulin treatment increased ZAG expression in neurons; this insulin-induced ZAG increase was abolished by either AXL1717 or BMS-754807. Either insulin treatment or ZAG overexpression suppressed epileptiform discharge-induced oxidative stress in neurons. Knock-down of ZAG abolished the antioxidative stress effect of insulin. Insulin-induced ZAG increase in neurons was mainly related to the activation of insulin-like growth factor-1 receptors. Insulin presented its antioxidative stress effect in neuronal epileptiform discharge models by increasing ZAG.

Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

* Xin Wei and Xi Liu contributed equally to the writing of this article.

Correspondence to Lifen Chen, PhD, MD, Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China Tel: +86 236 369 3088; fax: +86 236 371 1527; e-mail:

Received March 14, 2019

Accepted March 22, 2019

© 2019 Wolters Kluwer Health | Lippincott Williams & Wilkins