title: Combination of isoflurane and caspase inhibition reduces cerebral injury in rats subjected to focal cerebral ischemia.
abstract: BACKGROUND
  Recent data indicate that the neuroprotective efficacy of isoflurane is not sustained. Delayed neuronal death, mediated in part by apoptosis, contributes to the gradual increase in the size of the infarction. These data suggest that isoflurane may not be able to inhibit delayed neuronal death. The prevention of apoptosis by a caspase inhibitor might provide neuroprotection in addition to that provided by isoflurane. The current study was conducted to determine whether isoflurane-mediated neuroprotection can be made more durable with the administration of z-VAD-fmk, a nonspecific caspase inhibitor.
  
  
  METHODS
  Fasted Wister rats were allocated to awake-zVAD, awake-vehicle, isoflurane-zVAD, or isoflurane-vehicle groups (n = 16/group). Animals were subjected to focal ischemia for 60 min by filament occlusion of the middle cerebral artery. In the awake groups, isoflurane was discontinued after occlusion of the middle cerebral artery. In the isoflurane groups, isoflurane anesthesia was maintained at 1.5 minimum alveolar concentration during occlusion of the middle cerebral artery. Before and after ischemia, daily injections of z-VAD-fmk or vehicle were administered into the lateral cerebral ventricle for 14 days. Neurologic assessment was performed 14 days after ischemia. The volume of cerebral infarction and the number of intact neurons in the periinfarct cortex were determined by image analysis of hematoxylin and eosin-stained coronal brain sections.
  
  
  RESULTS
  Infarction volume was less in the isoflurane-zVAD group (23 +/- 11 mm, mean +/- SD) than in isoflurane-vehicle, awake-vehicle, and awake-zVAD groups (82 +/- 31, 86 +/- 31, and 59 +/- 25 mm, respectively; P < 0.05). In comparison with the awake-vehicle and isoflurane-vehicle groups, the administration of z-VAD-fmk significantly decreased infarction volume (P < 0.05). The infarction volume between the awake-vehicle and isoflurane-vehicle groups was not different. The number of intact neurons within the periinfarct cortex was significantly less in the awake-vehicle group than in the other three groups (P < 0.05). The isoflurane-zVAD group demonstrated better neurologic function than the awake-vehicle group (P < 0.05).
  
  
  CONCLUSIONS
  These findings are consistent with the premise that ongoing delayed neuronal death, in part mediated by apoptosis, contributes to the progression of cerebral infarction during the recovery period, and its inhibition can provide sustained neuroprotection.
authors.affiliation: Department of Anesthesiology, Veterans Affairs Medical Center and University of California, San Diego 92161, USA.
authors.forename: Satoki
authors.initials: S
authors.lastname: Inoue
authors.forename: John C
authors.initials: JC
authors.lastname: Drummond
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Davis
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cole
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use*; D018685:Anesthetics, Inhalation / Q000627:therapeutic use*; D000818:Animals; D001784:Blood Gas Analysis; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D007530:Isoflurane / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D018685:Anesthetics, Inhalation; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D007530:Isoflurane