The mitochondrial pathway of anesthetic isoflurane-induced apoptosis.

Abstract

The common inhalation anesthetic isoflurane has been shown to induce apoptosis, which then leads to accumulation of beta-amyloid protein, the hallmark feature of Alzheimer disease neuropathogenesis. The underlying molecular mechanism of the isoflurane-induced apoptosis is largely unknown. We, therefore, set out to assess whether isoflurane can induce apoptosis by regulating Bcl-2 family proteins, enhancing reactive oxygen species (ROS) accumulation, and activating the mitochondrial pathway of apoptosis. We performed these studies in cultured cells, primary neurons, and mice. Here we show for the first time that treatment with 2% isoflurane for 6 h can increase pro-apoptotic factor Bax levels, decrease anti-apoptotic factor Bcl-2 levels, increase ROS accumulation, facilitate cytochrome c release from the mitochondria to the cytosol, induce activation of caspase-9 and caspase-3, and finally cause apoptosis as compared with the control condition. We have further found that isoflurane can increase the mRNA levels of Bax and reduce the mRNA levels of Bcl-2. The isoflurane-induced ROS accumulation can be attenuated by the intracellular calcium chelator BAPTA. Finally, the anesthetic desflurane does not induce activation of mitochondrial pathway of apoptosis. These results suggest that isoflurane may induce apoptosis through Bcl-2 family proteins- and ROS-associated mitochondrial pathway of apoptosis. These findings, which have identified at least partially the molecular mechanism by which isoflurane induces apoptosis, will promote more studies aimed at studying the potential neurotoxic effects of anesthetics.

• Authors: Yiying Zhang, Yuanlin Dong, Xu Wu, Yan Lu, Zhipeng Xu, Andrew Knapp, Yun Yue, Tiejun Xu, Zhongcong Xie
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 6 Pg. 4025-4037 (Feb 05 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20007710 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Inhalation
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• Cytochromes c
• Isoflurane
• Caspase 3
• Caspase 9

Topics

• Anesthetics, Inhalation (pharmacology)
• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cells, Cultured
• Cytochromes c (metabolism)
• Cytosol (drug effects, metabolism)
• Enzyme Activation (drug effects)
• Female
• Humans
• In Situ Nick-End Labeling
• Isoflurane (pharmacology)
• Mice
• Mice, Inbred C57BL
• Microscopy, Fluorescence
• Mitochondria (drug effects, metabolism)
• Neurons (cytology, drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• bcl-2-Associated X Protein (genetics, metabolism)