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Role of Necroptosis, a Regulated Cell Death, in Seizure and Epilepsy

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Abstract

Epilepsy is a chronic neurological disease that is characterized by spontaneous and recurrent seizures. Regulated cell death is a controlled process and has been shown to be involved in neurodegenerative diseases. Necroptosis is a type of regulated cell death, and its association with epilepsy has been documented. Necroptosis signaling can be divided into two pathways: canonical and non-canonical pathways. Inhibition of caspase-8, dimerization of receptor-interacting protein kinase 1 (RIP1) and RIP3, activation of mixed-lineage kinase domain-like protein (MLKL), movement of MLKL to the plasma membrane, and cell rupture occurred in these pathways. Through literature review, it has been revealed that there is a relationship between seizure, neuroinflammation, and oxidative stress. The seizure activity triggers the activation of various pathways within the central nervous system, including TNF-α/matrix metalloproteases, Neogenin and Calpain/ Jun N-terminal Kinase 1, which result in distinct responses in the brain. These responses involve the activation of neurons and astrocytes, consequently leading to an increase in the expression levels of proteins and genes such as RIP1, RIP3, and MLKL in a time-dependent manner in regions such as the hippocampus (CA1, CA3, dentate gyrus, and hilus), piriform cortex, and amygdala. Furthermore, the imbalance in calcium ions, depletion of adenosine triphosphate, and elevation of extracellular glutamate and potassium within these pathways lead to the progression of necroptosis, a reduction in seizure threshold, and increased susceptibility to epilepsy. Therefore, it is plausible that therapeutic targeting of these pathways could potentially provide a promising approach for managing seizures and epilepsy.

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Acknowledgments

This study did not receive any financial support.

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This study did not receive any funding.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Parvaneh Mohseni-Moghaddam

  2. Department of Physiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran

    Hossein Khaleghzadeh-Ahangar

  3. Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

    Hossein Khaleghzadeh-Ahangar

  4. Shahid Fakouri High School, Department of Biology Education, Department of Education, Jouybar, Iran

    Rabi Atabaki

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  1. Parvaneh Mohseni-Moghaddam
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  2. Hossein Khaleghzadeh-Ahangar
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  3. Rabi Atabaki
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Contributions

RA contributed to the study’s conception and design. The introduction section of the manuscript was written by HKA, and all subsequent sections were written by RA in the first draft. HKA also contributed to the design of the figures. PMM commented on previous versions of the manuscript and provided valuable grammatical and scientific editing, as well as the initial idea for the study. The final version of the manuscript has been reviewed and approved by all authors.

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Correspondence to Rabi Atabaki.

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Mohseni-Moghaddam, P., Khaleghzadeh-Ahangar, H. & Atabaki, R. Role of Necroptosis, a Regulated Cell Death, in Seizure and Epilepsy. Neurochem Res 49, 1–13 (2024). https://doi.org/10.1007/s11064-023-04010-x

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