title: Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1.
abstract: BACKGROUND
  Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction.
  
  
  METHODS
  Multitracer micro-PET of ET1 focal ischemia in rats was performed using [11C]-flumazenil ([11C]FMZ) as a flow- and viability tracer and [18F]-fluoromisonidazole ([18F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [11C]FMZ-binding and [18F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex.
  
  
  RESULTS
  CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [11C]FMZ-binding was within the control range at all time points. Significant [18F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct.
  
  
  CONCLUSIONS
  ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.
authors.affiliation: Montreal Neurological Institute, Brain Imaging Center, McGill University, Montreal, Que., Canada.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.forename: Melvin
authors.initials: M
authors.lastname: Dea
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Heiss
authors.forename: Alexey
authors.initials: A
authors.lastname: Kostikov
authors.forename: Thomas
authors.initials: T
authors.lastname: Funck
authors.forename: Stephan
authors.initials: S
authors.lastname: Quessy
authors.forename: Barry
authors.initials: B
authors.lastname: Bedell
authors.forename: Numa
authors.initials: N
authors.lastname: Dancause
authors.forename: Alexander
authors.initials: A
authors.lastname: Thiel
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism*; D005442:Flumazenil / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D009044:Motor Cortex / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D019332:Endothelin-1; D005442:Flumazenil