Protective Effect of GIP against Monosodium Glutamate-Induced Ferroptosis in Mouse Hippocampal HT-22 Cells through the MAPK Signaling Pathway

Author:

Ko JiwonORCID,Jang Soyoung,Kwon Wookbong,Kim Si-YongORCID,Jang Soyeon,Kim Eungyung,Ji Young-RaeORCID,Park SijunORCID,Kim Myoung-Ok,Choi Seong-Kyoon,Cho Dong-Hyung,Lee Hyun-ShikORCID,Lim Su-GeunORCID,Ryoo Zae-Young

Abstract

The effect of glucose-dependent insulinotropic polypeptide (GIP) on cells under oxidative stress induced by glutamate, a neurotransmitter, and the underlying molecular mechanisms were assessed in the present study. We found that in the pre-treatment of HT-22 cells with glutamate in a dose-dependent manner, intracellular ROS were excessively generated, and additional cell damage occurred in the form of lipid peroxidation. The neurotoxicity caused by excessive glutamate was found to be ferroptosis and not apoptosis. Other factors (GPx-4, Nrf2, Nox1 and Hspb1) involved in ferroptosis were also identified. In other words, it was confirmed that GIP increased the activity of sub-signalling molecules in the process of suppressing ferroptosis as an antioxidant and maintained a stable cell cycle even under glutamate-induced neurotoxicity. At the same time, in HT-22 cells exposed to ferroptosis as a result of excessive glutamate accumulation, GIP sustained cell viability by activating the mitogen-activated protein kinase (MAPK) signalling pathway. These results suggest that the overexpression of the GIP gene increases cell viability by regulating mechanisms related to cytotoxicity and reactive oxygen species production in hippocampal neuronal cell lines.

Funder

National Research Foundation of Korea

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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