A mutation in β-amyloid precursor protein renders SH-SY5Y cells vulnerable to isoflurane toxicity: The role of inositol 1,4,5-trisphosphate receptors

• Published in: Molecular medicine reports Vol. 14; no. 6; pp. 5435 - 5442
• Main Authors: Liu, Xiang, Song, Shan, Wang, Qiujun, Yuan, Tianbao, He, Jihua
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01-12-2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Alveoli; Alzheimer's disease; Amyloid beta-protein; Amyloid beta-Protein Precursor - genetics; Amyloid precursor protein; Anesthesia; Anesthetics, Inhalation - pharmacology; Anesthetics, Inhalation - toxicity; Animal cognition; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Calcium (reticular); Calcium - metabolism; Cell culture; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; cells; Complications and side effects; Cytotoxicity; Development and progression; Drug allergy; Endoplasmic reticulum; Flow cytometry; Gene Expression; Gene mutations; Genetic aspects; Health aspects; Heart surgery; Homeostasis; Homeostasis - drug effects; Homeostasis - genetics; Humans; Inositol 1,4,5-trisphosphate receptors; Inositol 1,4,5-Trisphosphate Receptors - genetics; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Isoflurane; Isoflurane - pharmacology; Isoflurane - toxicity; Mutation; Neuroblastoma; Neurodegeneration; Neurodegenerative diseases; Neurotoxicity; Older people; Proteins; Risk factors; Rodents; Studies; Toxicity; Xestospongin C; β-Amyloid
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2016.5930

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.