Sevoflurane increases intracellular calcium to induce mitochondrial injury and neuroapoptosis

Abstract

Sevoflurane is commonly used in clinical anesthesia. However, some reports indicated that Sevoflurane could induce mitochondrial injury and neuroapoptosis. Although the mechanism remains unclear, evidence points to the increase of intracellular calcium after administration of Sevoflurane. Herein, we sought whether the increment of intracellular Ca²⁺ caused by Sevoflurane administration could induce mitochondrial injury and apoptosis in primary neurons of the hippocampus. Fluo-4-acetoxymethyl ester Ca²⁺ probe was used for measuring intracellular Ca²⁺ concentrations. LDH assay, CCK-8 assay, and Western blotting were performed to confirm Sevoflurane-induced neuroapoptosis. ROS, mPTP, and ATP production were assayed to reveal mitochondrial injury. Our results indicated that Sevoflurane increased intracellular Ca²⁺ and neuronal death. Sevoflurane also elevated ROS and the opening of mPTP, and decreased ATP production in neurons. The expression of cytochrome c, cleaved caspase-9, cleaved caspase-3, and the ratio of Bax/Bcl-2 were also increased. By using calcium channel blocker Nimodipine, the increase of intracellular Ca²⁺ was attenuated, and the death rate of neurons, the ROS and opening of mPTP, decreased ATP production, the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3 and the ratio of Bax/Bcl-2 were alleviated. Our study suggested that Sevoflurane could increase intracellular Ca²⁺ to induce mitochondrial injury and mitochondria-mediated neuroapoptosis in neurons.

Keywords: Apoptosis; Calcium; Mitochondrial injury; Neurotoxicity; Sevoflurane.