Pamiparib Induces Neurodevelopmental Defects and Cerebral Haemorrhage in Zebrafish Embryos via Inhibiting Notch Signalling

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 mu M 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.

Automated summary

This study demonstrates the neurotoxic effects of Pamiparib on zebrafish, including cerebral hemorrhage, brain atrophy, and movement disorders. Pamiparib exposure leads to downregulation of acetylcholinesterase and adenosine triphosphate activities, upregulation of oxidative stress, apoptosis, and disruption of gene expression involved in neurodevelopment, neurotransmitter pathways, and Parkinson's disease-like symptoms. Astaxanthin and activation of Notch signaling can partially rescue the neurodevelopmental defects caused by Pamiparib.