title: Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently.
abstract: Depletion of calcium from the neuronal endoplasmic reticulum (ER) induces apoptosis. Isoflurane depletes calcium from sarcoplasmic reticulum (SR) of muscle, an analogue of ER in neurons, while sevoflurane maintains or increases SR calcium. We hypothesized that isoflurane, but not sevoflurane, induces apoptosis by depleting the ER calcium. Rat PC12 pheochromocytoma cells and primary cortical neurons were treated with equipotent doses of isoflurane and sevoflurane. Isoflurane, but not sevoflurane, at equipotent doses induced cell damage determined by both LDH release and MTT reduction assays, dose and time dependently, in both types of cells. Isoflurane at 2.4% for 24 h induced cytotoxicity in both cell types, which was characterized by nuclear condensation and fragmentation and activation of caspases 3 and 9. Isoflurane cytotoxicity was suppressed by dantrolene, a ryanodine receptor antagonist that inhibits abnormal calcium release from the ER. Isoflurane decreased the Bcl-2/Bax ratio by as much as 36% (P < 0.05). However, sevoflurane did not cause neuronal damage by apoptosis nor did it decrease the Bcl-2/Bax ratio. These results suggest that isoflurane and sevoflurane differentially affect the Bcl-2/Bax ratio and cell survival. At equipotent concentrations, isoflurane, but not sevoflurane, induces cytotoxicity in both PC12 cells and primary cortical neurons and decreases the Bcl-2/Bax ratio.
authors.affiliation: Department of Anesthesia, 305 John Morgan Building, 3620 Hamilton Walk, University of Pennsylvania Health System, Philadelphia, PA 19104-4283, USA. weih@uphs.upenn.edu
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.forename: Baobin
authors.initials: B
authors.lastname: Kang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Wei
authors.forename: Ge
authors.initials: G
authors.lastname: Liang
authors.forename: Qing Cheng
authors.initials: QC
authors.lastname: Meng
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Li
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
mesh_terms: D000165:Acridine Orange; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007530:Isoflurane / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008738:Methyl Ethers / Q000494:pharmacology*; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D000077149:Sevoflurane; D051028:bcl-2-Associated X Protein
chemical_list: D018685:Anesthetics, Inhalation; C494828:Bax protein, rat; D008738:Methyl Ethers; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000077149:Sevoflurane; D007530:Isoflurane; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D000165:Acridine Orange; D003620:Dantrolene; D002118:Calcium