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Published on: November 20, 2015
Histone lactylation protects against sevoflurane-induced cognitive impairment by regulating YTHDF3/PRDX3 mediated
Yang Zhang1, Xiaowen Meng2, Weiming Zhao2
1Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006 Jiangsu Province, PR China; Institute of Anesthesiology, Soochow University, Suzhou 215006 Jiangsu Province, PR China; Department of Anesthesiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004 Anhui Province, PR China.
Background:
Sevoflurane (SEV), a widely used inhalational anesthetic, multiple SEV exposures has been implicated in cognitive impairment, particularly in neonates. However, the mechanisms underlying SEV-induced cognitive impairment not fully understood.
Methods:
Neonatal mice or murine microglial line BV-2 cells were exposed to SEV. Morris water maze and novel object recognition tests were used for measuring the cognitive function of mice. Histological examination and immunofluorescence staining were conducted to evaluate hippocampal morphology and the lactylated proteins in microglia, respectively. Cell pyroptosis was measured by flow cytometry and transmission electron microscope, and cytokine levels were detected using ELISA. Protein and gene expression were analyzed through western blot and RT-PCR. The interaction of proteins was verified by CHIP or RIP assays.
Results:
SEV induces significant cognitive impairment and reduces both histone lactylation and YTH domain-containing family protein 3 (YTHDF3) expression in the hippocampal tissues of neonatal mice. A decrease in histone lactylation and YTHDF3 expression is accompanied by increased cell pyroptosis and inflammation were observed in SEV-treated BV-2 cells. SEV modulates YTHDF3 expression via histone lactylation, thereby influencing N6-methyladenosine (m6A)-mediated peroxiredoxin 3 (PRDX3) translation and the subsequent activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome mediated pyroptosis in BV-2 cells. Overexpression of YTHDF3 or PRDX3 counteract the SEV-induced promotion of pyroptosis and inflammation in BV-2 cells. Furthermore, histone lactylation enhances YTHDF3 expression and mitigates SEV-induced cognitive dysfunction in neonatal mice, whereas downregulation of YTHDF3 diminishes this protective effect.
Conclusion:
Our findings elucidate that histone lactylation mitigates SEV-induced cognitive impairment by regulating YTHDF3/PRDX3-mediated microglial pyroptosis in neonatal mice. These insights offer a novel understanding of the molecular mechanisms underlying SEV-induced neurotoxicity in neonates.
Insights
Sevoflurane exposure impairs neonatal cognition by increasing microglial pyroptosis. Histone lactylation protects against this by regulating YTHDF3/PRDX3 pathways, mitigating neuroinflammation and cognitive deficits.
Area of Science:
- Neuroscience
- Molecular Biology
- Anesthesiology
Background:
- Sevoflurane (SEV) is a common anesthetic linked to neonatal cognitive impairment.
- The precise mechanisms behind SEV-induced cognitive dysfunction remain unclear.
Purpose of the Study:
- To investigate the role of histone lactylation and YTHDF3 in SEV-induced cognitive impairment in neonatal mice.
- To elucidate the molecular pathways, including microglial pyroptosis, involved in SEV neurotoxicity.
Main Methods:
- Neonatal mice and BV-2 microglial cells were exposed to sevoflurane.
- Cognitive function was assessed using behavioral tests (Morris water maze, novel object recognition).
- Molecular analyses included western blot, RT-PCR, immunofluorescence, flow cytometry, and transmission electron microscopy to evaluate histone lactylation, YTHDF3 expression, pyroptosis, and inflammation.
Main Results:
- SEV exposure impaired cognitive function and reduced histone lactylation and YTHDF3 expression in neonatal mice.
- SEV increased microglial pyroptosis and inflammation, linked to decreased histone lactylation and YTHDF3.
- Histone lactylation regulates YTHDF3, influencing PRDX3 translation and NLRP3 inflammasome activation, thereby controlling pyroptosis.
Conclusions:
- Histone lactylation mitigates SEV-induced cognitive impairment in neonates by inhibiting YTHDF3/PRDX3-mediated microglial pyroptosis.
- This study reveals a novel molecular mechanism for SEV neurotoxicity, highlighting histone lactylation as a potential therapeutic target.
