Mechanism of cell death pathways in status epilepticus and related therapeutic agents

Du, Ke; He, Miao; Zhao, Dongyi; Wang, Yuting; Ma, Chao; Liang, Hongyue; Wang, Wuyang; Min, Dongyu; Xue, Lei; Guo, Feng

doi:10.1016/j.biopha.2022.112875

Cited by 18 publications

(8 citation statements)

References 182 publications

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“…Evidence indicated that neural cell death exacerbates the onset and progression of SE [ 30 ]. Next, to explore the molecular mechanism of SE-induced hippocampal neuron death, we examined the changes in several main forms of cell death, including apoptosis, necroptosis, ferroptosis, and pyroptosis.…”

Section: Resultsmentioning

confidence: 99%

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

Ye,

Lin,

Chen

et al. 2024

Heliyon

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Section: Resultsmentioning

confidence: 99%

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

Ye,

Lin,

Chen

et al. 2024

Heliyon

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“…Necroptosis, a type of cell death also known as programmed necrosis, can be induced when TNFα binds to its receptor, TNFR1, and activates RIP1/3 to phosphorylate MLKL, an important marker of necroptosis ( Yu et al, 2021 ). Phosphorylated MLKL then forms an oligomer and binds to the cell membrane, causing Ca 2+ and Na + influx, and increasing extracellular permeation of cellular components including DAMPs, which eventually leads to cell death ( Du et al, 2022 ). Since SE is an inflammatory condition and cell deaths in SE in part showed necrotic morphologies ( Fujikawa et al, 2000a ; Dingledine et al, 2014 ; Wang et al, 2017b ; Cai et al, 2017 ; Fricker et al, 2018 ; Du et al, 2022 ), involvement of necroptosis has been assumed.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylated MLKL then forms an oligomer and binds to the cell membrane, causing Ca 2+ and Na + influx, and increasing extracellular permeation of cellular components including DAMPs, which eventually leads to cell death ( Du et al, 2022 ). Since SE is an inflammatory condition and cell deaths in SE in part showed necrotic morphologies ( Fujikawa et al, 2000a ; Dingledine et al, 2014 ; Wang et al, 2017b ; Cai et al, 2017 ; Fricker et al, 2018 ; Du et al, 2022 ), involvement of necroptosis has been assumed. Indeed, we reported the first evidence that acute seizures can cause MLKL-mediated necroptosis in the hippocampus, in addition to the involvement of truncated neogenin in this process ( Choi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures

et al. 2023

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Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we investigated the therapeutic effects of a novel small molecule, NecroX-7, in TLE using both a low [Mg2+]o-induced epileptiform activity model and a mouse model of pilocarpine-induced status epilepticus (SE). NecroX-7 post-treatment enhanced the viability of primary hippocampal neurons exposed to low [Mg2+]o compared to controls in an MTT assay. Application of NecroX-7 after pilocarpine-induced SE also reduced the number of degenerating neurons labelled with Fluoro-Jade B. Immunocytochemistry and immunohistochemistry showed that NecroX-7 post-treatment significantly alleviated ionized calcium-binding adaptor molecule 1 (Iba1) intensity and immunoreactive area, while the attenuation of reactive astrocytosis by glial fibrillary acidic protein (GFAP) staining was observed in cultured hippocampal neurons. However, NecroX-7-mediated morphologic changes of astrocytes were seen in both in vitro and in vivo models of TLE. Finally, western blot analysis demonstrated that NecroX-7 post-treatment after acute seizures could decrease the expression of mixed lineage kinase domain-like pseudokinase (MLKL) and phosphorylated MLKL (p-MLKL), markers for necroptosis. Taken all together, NecroX-7 has potential as a novel medication for TLE with its neuroprotective, anti-inflammatory, and anti-necroptotic effects.

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“…Biochemical and transcriptomic analyses of mediators of iron metabolism, antioxidant defenses, oxidative stress, and lipid peroxidation in experimental disease models, autopsy material, and induced pluripotent stem cell (iPSCs) derived from patients indicate that ferroptosis is a major mechanism of cell death in a wide range of neurologic disorders. These include Alzheimer disease (AD), 64,72,76-82 Parkinson disease (PD), 55,83-87 amyotrophic lateral sclerosis (ALS), 88-92 Huntington disease, 93-95 Friedreich ataxia, 96-98 multiple sclerosis, 99-101 ischemic stroke, 47,102-105 intracerebral hemorrhage, 106,107 traumatic brain injury, 108 spinal cord injury, 109,110 epilepsy, 111-113 and glioma, 114 among others. This topic has been extensively reviewed, 16-21,115,116 and only few concepts will be emphasized in this study.…”

Section: Role Of Ferroptosis In Neurologic Diseasementioning

confidence: 99%

What Is the Role of Ferroptosis in Neurodegeneration?

Benarroch

2023

Neurology

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Ferroptosis is a unique form of programmed cell death pathway that is mechanistically different from necrosis, apoptosis, or autophagy.1 Ferroptosis is induced by reactive oxygen species (ROS) originating from multiple sources, especially accumulation of free intracellular divalent iron (Fe2+), leading to peroxidation of polyunsaturated fatty acids (PUFAs) and resulting in membrane damage (Figure). One major trigger of ferroptosis is decreased availability of intracellular antioxidant enzymes, particularly glutathione peroxidases (GPXs).1-7 Because of its high lipid concentration and oxygen consumption rate, the nervous tissue is extremely vulnerable to oxidative damage and ferroptosis. With aging, iron accumulates in the brain, which predisposes to and exacerbates these processes.8 Iron promotes ferroptosis both directly and as a cofactor required for the activity of enzymes mediating redox reactions and lipid peroxidation.9,10 Epigenetic regulation can determine cell sensitivity to ferroptosis by affecting intracellular iron levels, oxidative stress, and lipid metabolism.11 Ferroptosis affects all cell types in the nervous system, including neurons, glial cells, and pericytes.12 Microglia are the primary iron-accumulating cells in disease.13,14 Recent evidence indicates that iron-laden microglia have a critical role in ferroptosis associated with neurodegeneration.15 Studies in vitro, in experimental disease models, and in human brain tissue indicate that iron accumulation, oxidative stress, and lipid peroxidation are major disease mechanisms in a wide range of neurologic disorders. These studies also suggest that the different components of the ferroptosis pathway are potential targets for therapeutic intervention. The mechanisms of ferroptosis and its role in neurologic disorders have been the subject of several recent comprehensive reviews.7,8,16-21 Some of these concepts pertinent to neurodegeneration will be emphasized in this study.

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Mechanism of cell death pathways in status epilepticus and related therapeutic agents

Cited by 18 publications

References 182 publications

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

SREBP1 deficiency diminishes glutamate-mediated HT22 cell damage and hippocampal neuronal pyroptosis induced by status epilepticus

Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures

What Is the Role of Ferroptosis in Neurodegeneration?

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