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

Frontiers in Pharmacology

Pharmacology

Minseo Kim¹  Yihyun Roh¹  Su Bin Lee²  Mi-Hye Kim²  Kyung-Ok Cho³  Hee Jung Kim⁴ 

[1] College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea;Department of Medical Laser, Graduate School, Dankook University, Cheonan, Republic of Korea;Department of Pharmacology, Catholic Neuroscience Institute, Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea;Department of Biomedicine and Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea;Department of Physiology, College of Medicine, Center for Human Risk Assessment, Dankook University, Cheonan, Republic of Korea;

关键词: NecroX-7;    neuroinflammation;    neuroprotection;    necroptosis;    excitotoxicity;    seizure;    hippocampus;   

DOI  :  10.3389/fphar.2023.1187819

 received in 2023-03-16, accepted in 2023-07-24,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Roh, Lee, Kim, Kim, Kim and Cho.