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

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 Ser 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 Ser, 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.