Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures
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 act...
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1187819/full |
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| author | Yihyun Roh Su Bin Lee Minseo Kim Mi-Hye Kim Hee Jung Kim Kyung-Ok Cho Kyung-Ok Cho |
| author_facet | Yihyun Roh Su Bin Lee Minseo Kim Mi-Hye Kim Hee Jung Kim Kyung-Ok Cho Kyung-Ok Cho |
| author_sort | Yihyun Roh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T18:01:00Z |
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| id | doaj.art-fe1ce44c95ec4268a1ab824b7bd063c2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T18:01:00Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-fe1ce44c95ec4268a1ab824b7bd063c22023-08-02T12:28:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-08-011410.3389/fphar.2023.11878191187819Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizuresYihyun Roh0Su Bin Lee1Minseo Kim2Mi-Hye Kim3Hee Jung Kim4Kyung-Ok Cho5Kyung-Ok Cho6College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaDepartment of Medical Laser, Graduate School, Dankook University, Cheonan, Republic of KoreaCollege of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaDepartment of Medical Laser, Graduate School, Dankook University, Cheonan, Republic of KoreaDepartment of Physiology, College of Medicine, Center for Human Risk Assessment, Dankook University, Cheonan, Republic of KoreaDepartment of Pharmacology, Catholic Neuroscience Institute, Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaDepartment of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul, Republic of KoreaTemporal 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.https://www.frontiersin.org/articles/10.3389/fphar.2023.1187819/fullNecroX-7neuroinflammationneuroprotectionnecroptosisexcitotoxicityseizure |
| spellingShingle | Yihyun Roh Su Bin Lee Minseo Kim Mi-Hye Kim Hee Jung Kim Kyung-Ok Cho Kyung-Ok Cho Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures Frontiers in Pharmacology NecroX-7 neuroinflammation neuroprotection necroptosis excitotoxicity seizure |
| title | Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures |
| title_full | Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures |
| title_fullStr | Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures |
| title_full_unstemmed | Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures |
| title_short | Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures |
| title_sort | alleviation of hippocampal necroptosis and neuroinflammation by necrox 7 treatment after acute seizures |
| topic | NecroX-7 neuroinflammation neuroprotection necroptosis excitotoxicity seizure |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1187819/full |
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