Pamiparib induces neurodevelopmental defects and cerebral haemorrhage in zebrafish embryos via inhibiting notch signaling

Abstract Pamiparib is a 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 hours post-fertilization (hpf). Results showed that Pamiparib can specifically induce cerebral haemorrhage, brain atrophy and movement disorders in fish larvae. In addition, Pamiparib exposure leads to down-regulation of acetylcholinesterase and ATPase activity, and up-regulation of oxidative stress which then leads to apoptosis and disrupts the gene expression involved in the neurodevelopment and neurotransmitter pathways.Meanwhile, astaxanthin can partially rescue neurodevelopmental defects by downregulating oxidative stress. After exposure to Pamiparib, the notch signaling is down-regulated, and the use of an activator of notch signaling can partially prevent neurodevelopmental toxicity. Therefore, our research indicates that Pamiparib may induce zebrafish neurotoxicity by down-regulating notch signalling related genes and inducing oxidative stress.