title: Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice.
abstract: OBJECTIVE
  Isoflurane, a volatile anesthetic agent, has been recognized for its potential neuroprotective properties and has antiapoptotic effects. We examined whether isoflurane posttreatment is protective against early brain injury after subarachnoid hemorrhage and determined whether this effect needs sphingosine-related pathway activation.
  
  
  METHODS
  Controlled in vivo laboratory study.
  
  
  METHODS
  Animal research laboratory.
  
  
  METHODS
  One hundred seventy-nine 8-wk-old male CD-1 mice weighing 30-38 g.
  
  
  METHODS
  Subarachnoid hemorrhage was induced in mice by endovascular perforation. Animals were randomly assigned to sham-operated, subarachnoid hemorrhage-vehicle, and subarachnoid hemorrhage+2% isoflurane. Neurobehavioral function and brain edema were evaluated at 24 and 72 hrs. The expression of sphingosine kinase, phosphorylated Akt, and cleaved caspase-3 was determined by Western blotting and immunofluorescence. Neuronal cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. Effects of a sphingosine kinase inhibitor N, N-dimethylsphingosine or a sphingosine 1 phosphate receptor inhibitor VPC23019 on isoflurane's protective action against postsubarachnoid hemorrhage early brain injury were also examined.
  
  
  RESULTS
  Isoflurane significantly improved neurobehavioral function and brain edema at 24 hrs but not 72 hrs after subarachnoid hemorrhage. At 24 hrs, isoflurane attenuated neuronal cell death in the cortex, associated with an increase in sphingosine kinase 1 and phosphorylated Akt, and a decrease in cleaved caspase-3. The beneficial effects of isoflurane were abolished by N, N-dimethylsphingosine and VPC23019.
  
  
  CONCLUSIONS
  Isoflurane posttreatment delays the development of postsubarachnoid hemorrhage early brain injury through antiapoptotic mechanisms including sphingosine-related pathway activation, implying its use for anesthesia during acute aneurysm surgery or intervention.
authors.affiliation: From the Departments of Physiology (OA, YH, PS, HS, NHK, JT, JHZ), and Neurosurgery (JHZ), Loma Linda University School of Medicine, Loma Linda, CA.
authors.forename: Orhan
authors.initials: O
authors.lastname: Altay
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Prativa
authors.initials: P
authors.lastname: Sherchan
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.forename: Nikan H
authors.initials: NH
authors.lastname: Khatibi
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001929:Brain Edema / Q000188:drug therapy; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D007530:Isoflurane / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy*; D000099157:Sphingosine Kinase
chemical_list: D007530:Isoflurane; D008246:Lysophospholipids; D018696:Neuroprotective Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate