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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\u00a0mg\/kg\/day can alleviate neurotoxicity in the brains of mice administered 50\u00a0ppm MeHg in drinking water for 5\u00a0weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2\u00a0weeks after the initiation of exposure to 30\u00a0ppm 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.<\/jats:p>","DOI":"10.1007\/s00204-024-03902-3","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:41:13Z","timestamp":1730090473000},"page":"563-574","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice"],"prefix":"10.1007","volume":"99","author":[{"given":"Ryohei","family":"Miki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Iijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobumasa","family":"Takasugi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatake","family":"Fujimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6562-2957","authenticated-orcid":false,"given":"Takashi","family":"Uehara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,27]]},"reference":[{"issue":"1","key":"3902_CR1","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S0065-3101(24)00072-0","volume":"43","author":"SW Brusilow","year":"1996","unstructured":"Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. 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All procedures involving animals were performed in accordance with the Guide for the Care and Use of Laboratory Animals issued by the National Institute for Minamata Disease and approved by the Animal Ethics and Management Committee of the National Institute for Minamata Disease (No. 050912 and 051221).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}