Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice.

IF 4.8 2区 医学 Q1 TOXICOLOGY
Ryohei Miki, Ryosuke Nomura, Yuta Iijima, Sho Kubota, Nobumasa Takasugi, Takao Iwawaki, Masatake Fujimura, Takashi Uehara
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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.

4- 苯丁酸对甲基汞诱导的小鼠神经细胞死亡的治疗潜力。
甲基汞(MeHg)是一种环境神经毒素,可诱发中枢神经系统损伤,是水俣病的致病因子。甲基汞的神经毒性机理在很大程度上仍然未知,因此需要有效的治疗药物,如针对甲基汞诱导的内质网(ER)应激和作为防御机制被激活的未折叠蛋白反应(UPR)的药物。我们研究了腹腔注射化学伴侣剂--4-苯基丁酸(4-PBA)120 毫克/千克/天是否能减轻在饮用水中添加 50 ppm MeHg 5 周的小鼠大脑的神经毒性。4-PBA 能明显减轻甲基汞引起的ER应激、神经细胞凋亡和神经症状。此外,即使在开始接触饮用水中的 30 ppm 甲基汞 2 周后施用 4-PBA 也是有效的。我们的研究结果有力地表明,ER应激和UPR是参与甲基汞毒性的关键过程,4-PBA是治疗甲基汞诱导的神经毒性的新型候选疗法。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
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.
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