title: Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures.
abstract: BACKGROUND
  Volatile anesthetics are known to ameliorate experimental ischemic brain injury. A possible mechanism is inhibition of excitotoxic cascades induced by excessive glutamatergic stimulation. This study examined interactions between volatile anesthetics and excitotoxic stress.
  
  
  METHODS
  Primary cortical neuronal-glial cultures were exposed to N-methyl-D-aspartate (NMDA) or glutamate and isoflurane (0.1-3.3 mM), sevoflurane (0.1-2.9 mM), halothane (0.1-2.9 mM), or 10 microM (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801). Lactate dehydrogenase release was measured 24 h later. In other cultures, effects of volatile anesthetics on Ca++ uptake and mitochondrial membrane potential were determined in the presence or absence of NMDA (0-200 microM).
  
  
  RESULTS
  Volatile anesthetics reduced excitotoxin induced lactate dehydrogenase release by up to 52% in a dose-dependent manner. At higher concentrations, this protection was reversed. When corrected for olive oil solubility, the three anesthetics offered equivalent protection. MK-801 provided near-complete protection. Ca++ uptake was proportionally reduced with increasing concentrations of anesthetic but did not account for reversal of protection at higher anesthetic concentrations. Given equivalent NMDA-induced Ca++ loads, cells treated with volatile anesthetic had greater lactate dehydrogenase release than those left untreated. At protective concentrations, volatile anesthetics partially inhibited NMDA-induced mitochondrial membrane depolarization. At higher concentrations, volatile anesthetics alone were sufficient to induce mitochondrial depolarization.
  
  
  CONCLUSIONS
  Volatile anesthetics offer similar protection against excitotoxicity, but this protection is substantially less than that provided by selective NMDA receptor antagonism. Peak effects of NMDA receptor antagonism were observed at volatile anesthetic concentrations substantially greater than those used clinically.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.forename: M
authors.initials: M
authors.lastname: Aono
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Massey
authors.forename: R D
authors.initials: RD
authors.lastname: Pearlstein
authors.forename: D S
authors.initials: DS
authors.lastname: Warner
mesh_terms: D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009457:Neuroglia / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D018685:Anesthetics, Inhalation; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D002118:Calcium