title: A mutation in β-amyloid precursor protein renders SH‑SY5Y cells vulnerable to isoflurane toxicity: The role of inositol 1,4,5‑trisphosphate receptors.
abstract: Isoflurane is a commonly used inhaled anesthetic, which induces apoptosis of SH‑SY5Y cells in a dose‑ and time‑dependent manner; however, the underlying mechanisms remain unknown. The authors of the present study hypothesized that a mutation in β‑amyloid precursor protein (APP), which is a gene associated with familial Alzheimer's disease, may render cells vulnerable to isoflurane‑induced cytotoxicity via activation of inositol 1,4,5‑trisphosphate receptors (IP3R). In the present study, SH‑SY5Y cells were transfected with a vector or with mutated APP, and were treated with the equivalent of 1 minimum alveolar concentration (MAC) isoflurane for 8 h. Cell apoptosis rate, alterations to cytosolic calcium concentrations ([Ca2+]c), and protein levels of IP3R were determined following exposure of cells to isoflurane. In addition, the effects of the IP3R antagonist xestospongin C were determined on isoflurane‑induced cytotoxicity and calcium release from the endoplasmic reticulum (ER) of mutated APP‑ and vector‑transfected SH‑SY5Y cells. Treatment with isoflurane (1 MAC) for 8 h induced a higher degree of cytotoxicity, and a marked increase in [Ca2+]c and IP3R protein levels in mutated APP‑transfected SH‑SY5Y cells compared with vector‑transfected SH‑SY5Y cells. Xestospongin C significantly attenuated isoflurane‑mediated cytotoxicity and inhibited calcium release from the ER of SH‑SY5Y cells. These results indicated that the APP mutation may render SH‑SY5Y cells vulnerable to isoflurane neurotoxicity, and the underlying mechanism may be associated with Ca2+ dysregulation via overactivation of IP3R.
authors.affiliation: Department of Anesthesiology, Children's Hospital of Hebei Province, Shijiazhuang, Hebei 050031, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Yantai Yu Huang Ding Hospital, Yantai, Shandong 264000, P.R. China.
authors.forename: Shan
authors.initials: S
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Tianbao
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Jihua
authors.initials: J
authors.lastname: He
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D018685:Anesthetics, Inhalation / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics*; D015870:Gene Expression; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D007530:Isoflurane / Q000494:pharmacology* / Q000633:toxicity; D009154:Mutation
chemical_list: D016564:Amyloid beta-Protein Precursor; D018685:Anesthetics, Inhalation; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007530:Isoflurane; D002118:Calcium