Statins impact primary embryonic mouse neural stem cell survival, cell death, and fate through distinct mechanisms

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Statins are cholesterol biosynthesis inhibitors used for cardiovascular disease prevention.
• Statins have anti-inflammatory effects, leading to trials for preeclampsia, despite pregnancy contraindications.
• Cholesterol biosynthesis pathway (CBP) products are crucial for developing neocortex neural stem-progenitor cell (NSPC) proliferation and differentiation.

Purpose of the Study:

• To investigate the effects of pravastatin and simvastatin on embryonic NSPC survival, proliferation, transcription, and cell fate in vitro.
• To elucidate the mechanisms underlying statin-induced impacts on the developing brain.

Main Methods:

• Primary embryonic NSPCs were treated with pravastatin and simvastatin in vitro.
• Cell survival, proliferation, and cell cycle progression were assessed.
• Genome-wide transcriptome analysis was performed.
• Co-treatment with farnesyl pyrophosphate (FPP) was used to investigate mechanisms.

Main Results:

• Statins dose-dependently decreased NSPC expansion by inducing cell death and autophagy in G1 phase.
• Pravastatin treatment increased CBP gene expression via SREBP2 activation.
• Farnesyl pyrophosphate reduced SREBP2 activation and PARP cleavage.
• Statins differentially altered NSPC cell fate and mRNA expression during differentiation via a non-CBP dependent pathway.

Conclusions:

• Statins negatively impact developing brain NSPCs through both CBP-dependent and independent mechanisms.
• Understanding these effects is crucial given statin use in pregnant populations.
• Further research is needed to fully characterize the risks and benefits of statin exposure during neurodevelopment.