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Isoflurane is one of the most popular inhalation anesthetics in the clinical practice but presenting an increased risk of neuronal injury. Hsp90 has been indicated to present an important role for maintaining neuronal homeostasis under the stress. However, the effect of hsp90 during isoflurane exposure is poorly understood. Here in this study, we aimed to observe the protect effect of hsp90 inhibition, and investigate the potential regulatory mechanism after isoflurane exposure. We found that hsp90 inhibitor, 17AAG, showed a great protective effect in maintaining isoflurane-induced ferroptosis of mice hippocampus and cultured neuronal cells. We focus on the crucial protein GPX4 activity in ferroptosis, and found that the 17 AAG contributed its protect effect to preserve physiological level of GPX4 activity under isoflurane exposure, although 17AAG could restored the protein level of GPX4. Further, we observed CMA pathway was activated and then mediated GPX4 degradation under isoflurane exposure. And 17AAG could interfere the complex between hsp90 and lamp2a to inhibit CMA activity, followed by blocking GPX4 degradation, which further affected the isoflurane-induced ferroptosis. Based on these findings, we proposed that hsp90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.

Background HSP90 has been shown to play an important role in maintaining neuronal homeostasis under stressful conditions. However, the effect of HSP90 during isoflurane exposure is unknown. This study aimed to investigate the protective effect of HSP 90 inhibition following isoflurane exposure and elucidate the potential regulatory mechanisms in vivo and in vitro. Methods Isoflurane-induced hippocampal neuron injury model was established in aged male C57BL/6 mice. After pretreatment with HSP90 inhibitor 17 AAG, the mice were administrated to isoflurane inhalation. Human neuroblastoma SH-SY5Y cells were pretreated with 17AAG and exposed to isoflurane. The hippocampal neuronal injury in mice were examined by HE staining and immunofluorescent staining. Cell viability in SH-SY5Y cells was examined by CCK8 assay and trypan blue staining. Ferroptosis biomarkers were investigated by transmission electron microscopy, flow cytometry, and western blot. We also detected the CMA signaling pathway to test the effect of HSP90 in isoflurane-induced neurotoxicity. Results The HSP90 inhibitor, 17 AAG, reduced isoflurane-induced ferroptosis in the mouse hippocampus and cultured neuronal cells. Isoflurane activated the CMA pathway, which then mediated GPX4 degradation. 17 AAG contributed to the preservation of GPX4 activity at physiological levels under isoflurane exposure. In addition, 17 AAG inhibits CMA activity and GPX4 degradation by preventing the formation of complexes between HSP90 and LAMP2A, thereby affecting isoflurane-induced ferroptosis. Conclusions HSP90 inhibition protects against isoflurane-induced neurotoxicity in vivo and vitro via inhibition of CMA pathway and GPX4 degradation, which induced ferroptosis and thus neuronal cell death.

Background: This study aimed to assess the effect of subcostal transversus abdominis plane (TAP) block on perioperative neuroendocrine stress response, postoperative analgesia, and recovery profiles in patients undergoing radical gastrectomy with general anesthesia. Methods: Sixty-five patients were recruited. Patients randomly received general anesthesia (control group), or general anesthesia combined with TAP block (40 mL of 0.375% ropivacaine) (TAP group). The primary endpoint was neuroendocrine levels including norepinephrine (NE), epinephrine (E), cortisol (Cor), glucose (Glu), interleukin (IL)-6 and IL-10 during 48 h after surgery. Secondary endpoints included pain score, hemodynamic variables and recovery characteristics. Results: Data from 61 of 65 patients were analyzed. The levels of NE, E, Cor, and Glu were blunt by TAP block during perioperative period. The levels of IL-6 and IL-10 were significantly lower in TAP group than in control group. TAP block efficiently relieved postoperative acute pain up to 12 h postoperatively with more stable perioperative hemodynamics compared with control group. Conclusions: Subcostal TAP block blunts perioperative stress response and provides efficient analgesia, with good hemodynamic stability and minimal adverse effects. Trial registration The trial was registered prior to patient enrollment at clinicaltrials.gov (NCT03035916, principal investigator: Guoqing Zhao, Ruizhu Liu, Kai Li, date of registration: 01/27/2017).