• In-Young Choi, ShimJae HyukJHDepartment of Physiology, College of Medicine, Dankook University, Cheonan, Republic of Korea; Department of Medical Laser, Graduate School, Dankook University, Cheonan, Republic of Korea., Mi-Hye Kim, Won Dong Yu, Yu Jin Kim, Gain Choi, Jae Ho Lee, Hee Jung Kim, and Kyung-Ok Cho.
• Department of Pharmacology, Department of Biomedicine & Health Sciences, Catholic Neuroscience Institute, Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
• Neuroscience. 2021 Aug 21; 470: 78-87.

AbstractProtecting hippocampal neurons from death after seizure activity is critical to prevent an alteration of neuronal circuitry and hippocampal function. Here, we present a novel target, a truncated form of neogenin that is associated with seizure-induced hippocampal necroptosis, and novel use of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) as a pharmacological regulator of neogenin truncation. We show that 3 days after pilocarpine-induced status epilepticus in mice, when hippocampal cell death is detected, the level of truncated neogenin is increased, while that of full-length neogenin is decreased. Moreover, phosphorylation of mixed lineage kinase domain-like pseudokinase, a crucial marker of necroptosis, was also markedly upregulated at 3 days post-status epilepticus. In cultured hippocampal cells, kainic acid treatment significantly reduced the expression of full-length neogenin. Notably, treatment with DAPT prevented neogenin truncation and protected cultured neurons from N-methyl-D-aspartate (NMDA)-induced death. These data suggest that seizure-induced hippocampal necroptosis is associated with the generation of truncated neogenin, and that prevention of this by DAPT treatment can protect against NMDA-induced excitotoxicity.Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

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