2. Academic Validation
  3. Pamiparib Induces Neurodevelopmental Defects and Cerebral Haemorrhage in Zebrafish Embryos via Inhibiting Notch Signalling

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

  • Mol Neurobiol. 2022 Nov;59(11):6652-6665. doi: 10.1007/s12035-022-02988-z.
Dou Yang 1 2,  Fasheng Liu 1,  Mengqi Wan 1,  Jieping Liu 1,  Ling Huang 1,  Chao Chen 1,  Xue Li 1,  Li Zhang 1,  Xiaobing Ding 3,  Xinjun Liao 1,  Guanghua Xiong 1,  Huiqiang Lu 1,  Juhua Xiao 4,  Zigang Cao 5
Affiliations

Affiliations

  • 1 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.
  • 2 College of Pharmacy, Nanchang University, Nanchang, 330027, Jiangxi, China.
  • 3 Affiliated Hospital of Jinggangshan University, Ji'an, 343000, Jiangxi Province, China.
  • 4 Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang University, Nanchang, 330006, Jiangxi, China.
  • 5 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. zigangcao@126.com.
PMID: 35982279 DOI: 10.1007/s12035-022-02988-z
Abstract

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.

Keywords

Cerebral haemorrhage; Neurodevelopment; Notch; Pamiparib; Zebrafish.

Figures
Products