RESUMO
Sevoflurane inhalation is prone to initiate cognitive deficits in infants. The early growth response-2 (Egr-2) gene is DNA-binding transcription factor, involving in cognitive function. In this study we explored the molecular mechanisms underlying the vulnerability to cognitive deficits after sevoflurane administration. Six-day-old (young) and 6-week-old (early adult) mice received anesthesia with 3% sevoflurane for 2 h daily for 3 days. We showed that multiple exposures of sevoflurane induced significant learning ability impairment in young but not early adult mice, assessed in Morris water maze test on postnatal days 65. The integrated differential expression analysis revealed distinct transcription responses of Egr family members in the hippocampus of the young and early adult mice after sevoflurane administration. Particularly, Egr2 was significantly upregulated after sevoflurane exposure only in young mice. Microinjection of Egr2 shRNA recombinant adeno-associated virus into the dentate gyrus alleviated sevoflurane-induced cognitive deficits, and abolished sevoflurane-induced dendritic spins loss and BDNF downregulation in young mice. On the contrary, microinjection of the Egr2 overexpression virus in the dentate gyrus aggravated learning ability impairment induced by sevoflurane in young mice but not early adult mice. Furthermore, we revealed that sevoflurane markedly upregulated the nuclear factors of activated T-cells NFATC1 and NFATC2 in young mice, which were involved in Egr2 regulation. In conclusion, Egr2 serves as a critical factor for age-dependent vulnerability to sevoflurane-induced cognitive deficits.
Assuntos
Anestésicos Inalatórios , Disfunção Cognitiva , Proteína 2 de Resposta de Crescimento Precoce , Éteres Metílicos , Animais , Camundongos , Anestésicos Inalatórios/toxicidade , Animais Recém-Nascidos , Cognição , Disfunção Cognitiva/induzido quimicamente , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Hipocampo/metabolismo , Aprendizagem em Labirinto , Sevoflurano/efeitos adversosRESUMO
AIM: The inhaled anesthetic sevoflurane may induce cognitive impairment in both animals and humans. Previous study has shown that sevoflurane triggers ER stress and may lead to apoptosis in rat hippocampal neurons. In this study, we examined whether sevoflurane caused autophagy and its contributions to sevoflurane induced neuronal cell injury. METHODS: H4 human neuroglioma cells were exposed to 4.1% sevoflurane for 6 h. Cell viability and apoptosis ratio were assessed using a CCK8 kit and flow cytometry, respectively. Autophagosomes in the cells were detected using GFP-LC3 plasmid transfection or transmission electronic microscopy. The expression of LC3B, p62/SQSTM, C/EBP homologous protein (CHOP) and glucose-related protein 78 (GRP78) was assessed with Western blotting. RESULTS: Sevoflurane treatment induced apoptosis and markedly increased the LC3-II level and GFP-LC3 puncta number, decreased p62 expression in H4 cells. Activation of autophagy by rapamycin (1 µmol/L) significantly reduced sevoflurane-induced apoptosis and increased cell viability, whereas inhibition of autophagy with 3-MA (5 mmol/L) caused the opposite effects. Furthermore, sevoflurane treatment markedly increased the expression of CHOP and GRP78, two hallmark proteins of ER stress. Inhibition of ER stress by 4-phenylbutyrate (500 µmol/L) abrogated sevoflurane-induced autophagy and apoptosis, and improved the viability. Moreover, sevoflurane-stimulated expression of CHOP and GRP78 was inhibited by rapamycin, but further enhanced by 3-MA. CONCLUSION: Sevoflurane treatment induces ER stress and activates autophagy, which antagonizes sevoflurane-induced apoptosis in H4 human neuroglioma cells. The results suggest that autophagy may be a potential therapeutic target in preventing sevoflurane-induced neurotoxicity.
Assuntos
Anestésicos Inalatórios/toxicidade , Autofagia/efeitos dos fármacos , Éteres Metílicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Sevoflurano , Sirolimo/farmacologiaRESUMO
BACKGROUND: Difficult airway is a significant cause of anesthesia-associated death and disability. Currently, physical examinations of thyromental distance, mouth opening, Mafampaii classification, etc. combined with X-ray, computed tomography (CT), and other imaging technologies are mainly used to evaluate difficult airways. However, in many special cases, i.e., emergency surgery, imaging examinations cannot be completed preoperatively. Such patients' airway can only be evaluated through general physical examination, which inevitably increases the likelihood of an unexpected difficult airway during anesthesia. CASE SUMMARY: We report a rare case of difficult intubation because of severe upper trachea distortion after induction. Emergency holmium laser lithotripsy was performed under transurethral ureteroscopy because the patient had anuria for 4 d and a creatinine level of 890 µmol/L. Due to the urgency of the condition, chest radiography or chest CT was not examined before surgery and the anesthesiologist did not evaluate the airway adequately, resulting in an unexpected difficult airway. CONCLUSION: The incidence of tracheal malformation and tracheal stenosis is extremely low, but the risk of hypoxia and even death due to difficult airways is extremely high for such patients. It is recommended to complete preoperative imaging examinations of the airway. For life-threatening emergency patients, a pre-anesthesia reassessment should be performed and surgeons should be prepared to prevent and manage the difficult airway.