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  3. Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis

Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis

  • Free Radic Biol Med. 2022 Mar;181:72-81. doi: 10.1016/j.freeradbiomed.2022.01.031.
Jinsheng Liu 1,  Li Li 2,  Ping Xie 3,  Xiaoyan Zhao 1,  Dongjing Shi 1,  Yan Zhang 4,  Chuxiong Pan 5,  Tianzuo Li 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 2 Department of Gastroenterology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 3 Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.
  • 4 College of Life Science, Peking University, Beijing, China.
  • 5 Department of Anesthesiology, Beijing Stomatological Hospital, Capital Medical University, Beijing, China. Electronic address: pandedao@126.com.
  • 6 Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China. Electronic address: trmzltz888@163.com.
PMID: 35122996 DOI: 10.1016/j.freeradbiomed.2022.01.031
Abstract

Mitochondria damage and Apoptosis were found associated with sevoflurane induced neurotoxicity in developing brains of rodent and neuro cell lines. The detailed upstream mechanism remains unclear. This study explored whether sevoflurane induces neurotoxicity by activating a GSK3β (glycogen synthase kinase 3β)/Drp1 (dynamin-related protein-1)-dependent mitochondrial fission and Apoptosis. Our results showed that sevoflurane exposure promoted mitochondria fission in hippocampus of neonatal mice, resulted in a prolonged escape latency from P32 (32-day-postnatal) to P35, and decreased platform crossing times on P36 as compared to the control treatment. Additionally, sevoflurane upregulated GSK3β stability and activation, promoted phosphorylation of Drp1 at Ser616 along with its translocation to mitochondria and resulted in increasing cytochrome c and cleaved casepase-3 in hippocampus of neonatal mice and in human SK-N-SH cells. Simultaneously, sevoflurane promoted the interaction between Drp1 and GSK3β. Furthermore, GSK3β activated phosphorylation of Drp1 at Ser616, induced mitochondrial fission, loss of mitochondrial membrane potential (MMP) and Apoptosis in SK-N-SH cells, which was attenuated by TDZD-8, an inhibitor of GSK3β. In conclusion, sevoflurane induced neurotoxicity links to a GSK3β/Drp1 dependent mitochondrial fission and Apoptosis.

Keywords

Apoptosis; Drp1 protein; Glycogen Synthase Kinase 3 beta; Mitochondria; Mitochondrial fission; Neurotoxicity; Sevoflurane.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15534
    99.0%, Mitochondrial Membrane Potential Probe