Hypoxia plays a significant role in the development of various cerebral diseases, many of which are associated with the potential risk of recurrence due to mitochondrial damage. Conventional drug treatments are not always effective for hypoxia-related brain diseases, necessitating the exploration of alternative compounds. In this study, we investigated the potential of diphenyl diselenide [(PhSe)₂] to ameliorate locomotor impairments and mitigate brain mitochondrial dysfunction in zebrafish subjected to hypoxia. Additionally, we explored whether these improvements could confer resistance to recurrent hypoxia. Through a screening process, an appropriate dose of (PhSe)₂ was determined, and animals exposed to hypoxia received a single intraperitoneal injection of 100 mg/kg of the compound or vehicle. After 1 h from the injection, evaluations were conducted on locomotor deficits, (PhSe)₂ content, mitochondrial electron transport system, and mitochondrial viability in the brain. The animals were subsequently exposed to recurrent hypoxia to assess the latency time to hypoxia symptoms. The findings revealed that (PhSe)₂ effectively crossed the blood–brain barrier, attenuated locomotor deficits induced by hypoxia, and improved brain mitochondrial respiration by modulating complex III. Furthermore, it enhanced mitochondrial viability in the telencephalon, contributing to greater resistance to recurrent hypoxia. These results demonstrate the beneficial effects of (PhSe)₂ on both hypoxia and recurrent hypoxia, with cerebral mitochondria being a critical target of its action. Considering the involvement of brain hypoxia in numerous pathologies, (PhSe)₂ should be further tested to determine its effectiveness as a potential treatment for hypoxia-related brain diseases.

Graphical Abstract

中文翻译：

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二苯基二硒化物可减轻初始缺氧期间的线粒体损伤并增强对反复缺氧的抵抗力

缺氧在各种脑部疾病的发生中起着重要作用，其中许多疾病与线粒体损伤导致的潜在复发风险有关。传统的药物治疗对于缺氧相关的脑部疾病并不总是有效，因此需要探索替代化合物。在这项研究中，我们研究了二苯基二硒化物 [(PhSe) ₂ ] 改善缺氧斑马鱼运动障碍和减轻脑线粒体功能障碍的潜力。此外，我们还探讨了这些改进是否可以抵抗反复缺氧。通过筛选过程，确定了 (PhSe) ₂的适当剂量，暴露于缺氧的动物​​接受单次腹膜内注射 100 mg/kg 的化合物或载体。注射1小时后，对大脑中的运动缺陷、(PhSe) ₂含量、线粒体电子传递系统和线粒体活力进行评估。随后将动物暴露于反复缺氧中以评估缺氧症状的潜伏时间。研究结果表明，(PhSe) ₂有效穿过血脑屏障，减轻缺氧引起的运动缺陷，并通过调节复合物 III 改善脑线粒体呼吸。此外，它还增强了端脑线粒体的活力，有助于增强对反复缺氧的抵抗力。这些结果证明了 (PhSe) ₂对缺氧和反复缺氧的有益作用，其中脑线粒体是其作用的关键目标。考虑到脑缺氧与多种病理学有关，应进一步测试 (PhSe) ₂以确定其作为缺氧相关脑部疾病的潜在治疗方法的有效性。

图形概要