title: Isoflurane but not sevoflurane or desflurane aggravates injury to neurons in vitro and in vivo via p75NTR-NF-ĸB activation.
abstract: BACKGROUND
  General anesthesia in patients with or at risk for neuronal injury remains challenging due to the controversial influence of volatile anesthetics on neuronal damage. We hypothesized that isoflurane, sevoflurane, and desflurane would exert variable degrees of neurotoxicity in vitro and in vivo via activation of the p75 neurotrophin receptor (p75).
  
  
  METHODS
  SH-SY5Y cells were exposed to oxygen-glucose deprivation (OGD, 16 hours), preceded or followed by incubation with isoflurane, sevoflurane, or desflurane (1.2 minimal alveolar concentration, 2 hours). Neuronal cell death was analyzed by flow cytometry (mitochondrial membrane potential, Annexin V/propidium iodide [AV/Pi]) and quantification of lactate dehydrogenase release. We analyzed NF-κB activity by DNA-binding ELISA and luciferase assay. The role of p75 was studied using the p75-blocking peptide TAT-pep5 and siRNA knockdown. The effect of isoflurane ±p75 inhibition on retinal ischemia-reperfusion injury (IRI) in adult Sprague-Dawley rats was assessed by analyzing retinal ganglion cell (RGC) density.
  
  
  RESULTS
  Isoflurane but not sevoflurane or desflurane postexposure aggravated OGD-induced neuronal cell death (AV/Pi positive cells: OGD 41.1% [39.0/43.3] versus OGD + isoflurane 48.5% [46.4/63.4], P = 0.001). Isoflurane significantly increased NF-κB DNA-binding and transcriptional activity of NF-κB (relative Luminescence Units: OGD 500 [499/637] versus OGD + isoflurane 1478 [1363/1643], P = 0.001). Pharmacological inhibition or siRNA knockdown of p75 counteracted the aggravating effects of isoflurane. Isoflurane increased RGC damage in vivo (IRI 1479 RGC/mm(2) [1311/1697] versus IRI + isoflurane 1170 [1093/1211], P = 0.03), which was counteracted by p75-inhibition via TAT-pep5 (P = 0.02).
  
  
  CONCLUSIONS
  Isoflurane but not sevoflurane or desflurane postexposure aggravates neurotoxicity in preinjured neurons via activation of p75 and NF-κB. These findings may have implications for the choice of volatile anesthetic being used in patients with or at risk for neuronal injury, specifically in patients with a stroke or history of stroke and in surgical procedures in which neuronal injury is likely to occur, such as cardiac surgery and neurovascular interventions.
authors.affiliation: From the *Department of Anesthesiology and Intensive Care Medicine, University Medical Center Freiburg, Freiburg, Germany; †Eye Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; and ‡Institute of Forensic Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Schallner
authors.forename: Felix
authors.initials: F
authors.lastname: Ulbrich
authors.forename: Helen
authors.initials: H
authors.lastname: Engelstaedter
authors.forename: Julia
authors.initials: J
authors.lastname: Biermann
authors.forename: Volker
authors.initials: V
authors.lastname: Auwaerter
authors.forename: Torsten
authors.initials: T
authors.lastname: Loop
authors.forename: Ulrich
authors.initials: U
authors.lastname: Goebel
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000077335:Desflurane; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000172:deficiency; D006801:Humans; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D008738:Methyl Ethers / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D016328:NF-kappa B; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; C068313:Ngfr protein, rat; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane; D005947:Glucose