title: The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity.
abstract: BACKGROUND
  Concerns have risen regarding the potential side effects of clinical exposure of the pediatric population to inhalational anesthetics, and how they might impact cognitive, learning, and memory functions. However, neither the mechanisms of anesthetic cytotoxicity, nor potential protective strategies, have yet been fully explored. In this study, we examined whether two of the most commonly used inhalational anesthetics, sevoflurane and desflurane, affect neuronal viability and synaptic network assembly between cultured rat cortical neurons.
  
  
  RESULTS
  Primary rat cortical neuron cultures were exposed to equipotent sevoflurane or desflurane for 1 hour. Neuron viability, synaptic protein expression, mitochondrial morphology, and neurite growth were assayed with immunostaining and confocal microscopy techniques. The effects of anesthetics on the functional development of neural networks were evaluated with whole-cell patch clamp recordings of spontaneous synaptic currents. Our results demonstrate that an acute exposure to sevoflurane and desflurane inhibits the development of neurite processes, impacts the mitochondria, and compromises synaptic proteins - concomitant with a reduction in synaptic function in mature networks. Interestingly, pretreatment of neurons with a mitochondrial division inhibitor (Mdivi-1) not only protected mitochondria integrity but also played a protective role against anesthetic-induced structural and functional neurotoxicity.
  
  
  CONCLUSIONS
  We show that Mdivi-1 likely plays a protective role against certain harmful effects of general anesthetics on primary rat neuronal cultures. In addition, Mdivi-1 alone plays a direct role in enhancing growth and modulating synaptic activity. This study highlights the importance of further study into possible protective agents against anesthetic neurotoxicity.
authors.affiliation: Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada. fenglianxu@slu.edu.|The Department of Biology, College of Arts and Sciences, Saint Louis University, Saint Louis, MO, 63103-2010, USA. fenglianxu@slu.edu.
authors.forename: Fenglian
authors.initials: F
authors.lastname: Xu
authors.affiliation: Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: Ryden
authors.initials: R
authors.lastname: Armstrong
authors.affiliation: Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Urrego
authors.affiliation: Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: Munir
authors.initials: M
authors.lastname: Qazzaz
authors.affiliation: The Department of Anesthesiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Pehar
authors.affiliation: The Department of Anesthesiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: J N
authors.initials: JN
authors.lastname: Armstrong
authors.affiliation: The Departments of Medical Genetics and Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada.
authors.forename: Tim
authors.initials: T
authors.lastname: Shutt
authors.affiliation: Hotchkiss Brain Institute and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 2T9, Canada. nisyed@ucalgary.ca.|The Department of Cell Biology & Anatomy and the Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 4Z6, Canada. nisyed@ucalgary.ca.
authors.forename: Naweed
authors.initials: N
authors.lastname: Syed
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D002470:Cell Survival; D000077335:Desflurane; D007530:Isoflurane / Q000031:analogs & derivatives / Q000494:pharmacology; D008322:Mammals / Q000378:metabolism*; D008738:Methyl Ethers / Q000494:pharmacology; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D052999:Quinazolinones; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane
keywords: Desflurane; General anesthetics; Mitochondria; Neurotoxicity; Sevoflurane; Synapse