Zhejiang Clinical Research Center for Mental Disorders, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Institute of Aging, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China.
Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang, 325000, China.
Ecotoxicol Environ Saf. 2023 Jan 1;249:114340. doi: 10.1016/j.ecoenv.2022.114340. Epub 2022 Dec 9.
The use of clinical psychoactive drugs often poses unpredictable threats to fetal development. Catechol-O-methyltransferase (COMT) is a key enzyme that regulates dopamine metabolism and a promising target for modulation of cognitive functions. Opicapone, a newly effective third-generation peripheral COMT inhibitor, is used for the treatment of Parkinson's disease (PD) and possibly to improve other dopamine-related disorders such as alcohol use disorder (AUD) and obsessive-compulsive disorder (OCD). The widespread use of opicapone will inevitably lead to biological exposure and damage to the human body, such as affecting fetal development. However, the effect of opicapone on embryonic development remains unknown. Here, zebrafish larvae were used as an animal model and demonstrated that a high concentration (30 μM) of opicapone exposure was teratogenic and lethal, while a low concentration also caused developmental delay such as a shortened body size, a smaller head, and reduced locomotor behaviors in zebrafish larvae. Meanwhile, opicapone treatment specifically increased the level of dopamine (DA) in zebrafish larvae. The depletion response of the total glutathione level (including oxidized and reduced forms of glutathione) and changed antioxidant enzymes activities in zebrafish larvae suggest oxidative damage caused by opicapone. In addition, enhanced glutathione metabolism and cytokine-cytokine receptor interaction were found in zebrafish larvae treated with opicapone, indicating that opicapone treatment caused an oxidation process and immune responses. Our results provide a new insight into the significant developmental toxicity of opicapone in zebrafish larvae.
临床精神活性药物的使用常常对胎儿发育构成不可预测的威胁。儿茶酚-O-甲基转移酶（COMT）是调节多巴胺代谢的关键酶，也是调节认知功能的有前途的靶点。新型有效第三代外周 COMT 抑制剂奥匹卡朋用于治疗帕金森病（PD），并可能改善其他与多巴胺相关的疾病，如酒精使用障碍（AUD）和强迫症（OCD）。奥匹卡朋的广泛使用将不可避免地导致生物暴露和对人体的损害，例如影响胎儿发育。然而，奥匹卡朋对胚胎发育的影响尚不清楚。在这里，我们使用斑马鱼幼虫作为动物模型，证明高浓度（30 μM）奥匹卡朋暴露具有致畸性和致死性，而低浓度也会导致发育迟缓，如斑马鱼幼虫的体型缩短、头部变小和运动行为减少。同时，奥匹卡朋处理特异性增加了斑马鱼幼虫中的多巴胺（DA）水平。总谷胱甘肽水平（包括氧化和还原形式的谷胱甘肽）的耗竭反应以及斑马鱼幼虫抗氧化酶活性的变化表明奥匹卡朋引起氧化损伤。此外，在奥匹卡朋处理的斑马鱼幼虫中发现增强的谷胱甘肽代谢和细胞因子-细胞因子受体相互作用，表明奥匹卡朋处理引起氧化过程和免疫反应。我们的结果为奥匹卡朋在斑马鱼幼虫中具有重要的发育毒性提供了新的见解。
