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.