Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs, College of Life Sciences, Jinggangshan University, Ji'an, 343009, Jiangxi, China.
College of Pharmacy, Nanchang University, Nanchang, 330027, Jiangxi, China.
Mol Neurobiol. 2022 Nov;59(11):6652-6665. doi: 10.1007/s12035-022-02988-z. Epub 2022 Aug 19.
Pamiparib is a poly ADP-ribose polymerase (PARP) inhibitor used in clinical studies, which can penetrate the blood-brain barrier efficiently. At present, there are few studies on its effect on vertebrate neurodevelopment. In this study, we exposed zebrafish embryos to 1, 2 and 3 µM of Pamiparib from 6 to 72 h post-fertilisation (hpf). Results showed that pamiparib can specifically induce cerebral haemorrhage, brain atrophy and movement disorders in fish larvae. In addition, pamiparib exposure leads to downregulation of acetylcholinesterase (AChE) and adenosine triphosphate (ATPase) activities, and upregulation of oxidative stress which then leads to apoptosis and disrupts the gene expression involved in the neurodevelopment, neurotransmitter pathways and Parkinson's disease (PD) like symptoms. Meanwhile, astaxanthin can partially rescue neurodevelopmental defects by downregulating oxidative stress. After exposure to pamiparib, the Notch signalling is downregulated, and the use of an activator of Notch signalling can partially rescue neurodevelopmental toxicity. Therefore, our research indicates that pamiparib may induce zebrafish neurotoxicity by downregulating Notch signalling and provides a reference for the potential neurotoxicity of pamiparib during embryonic development.
帕米帕利是一种多聚 ADP-核糖聚合酶（PARP）抑制剂，用于临床研究，能够有效地穿透血脑屏障。目前，关于其对脊椎动物神经发育影响的研究较少。在这项研究中，我们将斑马鱼胚胎暴露于 1、2 和 3μM 的帕米帕利中，从受精后 6 到 72 小时（hpf）。结果表明，帕米帕利可以特异性诱导鱼仔的脑内出血、脑萎缩和运动障碍。此外，帕米帕利暴露导致乙酰胆碱酯酶（AChE）和三磷酸腺苷酶（ATPase）活性下调，氧化应激上调，导致细胞凋亡，破坏与神经发育、神经递质通路和帕金森病（PD）样症状相关的基因表达。同时，虾青素通过下调氧化应激可以部分挽救神经发育缺陷。暴露于帕米帕利后，Notch 信号通路下调，使用 Notch 信号通路的激活剂可以部分挽救神经发育毒性。因此，我们的研究表明，帕米帕利可能通过下调 Notch 信号通路诱导斑马鱼神经毒性，并为帕米帕利在胚胎发育过程中的潜在神经毒性提供参考。
