Inhibiting specificity protein 1 attenuated sevoflurane-induced mitochondrial stress and promoted autophagy in hippocampal neurons through PI3K/Akt/mTOR and α7-nAChR signaling

Abstract

Sevoflurane, a commonly used anesthetic in surgery, is considered as an inducer of neurodegenerative diseases and postoperative complications including postoperative cognitive dysfunction. Evidence showed that specificity protein 1 (SP1) participated in the regulation of various cellular processes. Also, SP1 was found to modulate sevoflurane-induced hippocampal inflammatory injury both in vitro and in vivo. Our study aimed to illustrate the role of SP1 in mediating mitochondrial stress and autophagy in neurons under sevoflurane exposure. SiRNA for SP1 was transfected in to hippocampus neurons for the loss-of-function assay before sevoflurane stimulation. Meanwhile, recilisib was utilized for PI3K/Akt/mTOR signaling activation, GTS-21 and MLA (methylycaconitine citrate) were used to activate or inactivate alpha 7 nicotinic acetylcholine receptor (α7-nAChR), respectively. Sevoflurane induced SP1 upregulation and autophagy suppression. Interfering SP1 dramatically depressed the promoted oxidative stress and mitochondrial dysfunction induced by sevoflurane. Additionally, SP1 silence blocked sevoflurane-induced activation of PI3K/Akt/mTOR signaling and inhibition of α7-nAChR. Restoring PI3K/Akt/mTOR signaling or depressing CAP significantly reversed the repressive effects of SP1 knockdown on mitochondrial stress and autophagy imbalance in hippocampal cells. In conclusions, our research indicated that SP1 regulated sevoflurane-induced oxidative stress dysregulation, mitochondrial function and cell autophagy in hippocampus via mediating the PI3K/Akt/mTOR and α7-nAChR pathways. Therefore, it might provide a novel sight for sevoflurane-induced hippocampus injury and POCD therapy.