{"title":"Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice.","authors":"Ryohei Miki, Ryosuke Nomura, Yuta Iijima, Sho Kubota, Nobumasa Takasugi, Takao Iwawaki, Masatake Fujimura, Takashi Uehara","doi":"10.1007/s00204-024-03902-3","DOIUrl":null,"url":null,"abstract":"<p><p>Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.</p>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00204-024-03902-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"TOXICOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.
期刊介绍:
Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.