title: Sonothrombolysis with BR38 Microbubbles Improves Microvascular Patency in a Rat Model of Stroke.
abstract: BACKGROUND
  Early recanalization of large cerebral vessels in ischemic stroke is associated with improved clinical outcome, however persisting hypoperfusion leads to poor clinical recovery despite large vessel recanalization. Limited experimental sonothrombolysis studies have shown that addition of microbubbles during treatment can improve microvascular patency. We aimed to determine the effect of two different microbubble formulations on microvascular patency in a rat stroke model.
  
  
  METHODS
  We tested BR38 and SonoVue® microbubble-enhanced sonothrombolysis in Wistar rats submitted to 90-minute filament occlusion of the middle cerebral artery. Rats were randomized to treatment (n = 6/group): control, rt-PA, or rt-PA+3-MHz ultrasound insonation with BR38 or SonoVue® at full or 1/3 dose. Treatment duration was 60 minutes, beginning after withdrawal of the filament, and sacrifice was immediately after treatment. Vascular volumes were evaluated with microcomputed tomography.
  
  
  RESULTS
  Total vascular volume of the ipsilateral hemisphere was reduced in control and rt-PA groups (p<0.05), but was not significantly different from the contralateral hemisphere in all microbubble-treated groups (p>0.1).
  
  
  CONCLUSIONS
  Microbubble-enhanced sonothrombolysis improves microvascular patency. This effect is not dose- or microbubble formulation-dependent suggesting a class effect of microbubbles promoting microvascular reopening. This study demonstrates that microbubble-enhanced sonothrombolysis may be a therapeutic strategy for patients with persistent hypoperfusion of the ischemic territory.
authors.affiliation: Heart and Brain Research Group, Justus-Liebig-University, Giessen, Germany.|Department of Neurology, Justus-Liebig-University, Giessen, Germany.|Department of Cardiac Surgery, Kerckhoff Clinic, Bad Nauheim, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schleicher
authors.affiliation: Heart and Brain Research Group, Justus-Liebig-University, Giessen, Germany.|School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tomkins
authors.affiliation: Department of Diagnostic and Interventional Radiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Kampschulte
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Hyvelin
authors.affiliation: Bracco Suisse S.A., Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Botteron
authors.affiliation: Heart and Brain Research Group, Justus-Liebig-University, Giessen, Germany.|Department of Neurology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Juenemann
authors.affiliation: Heart and Brain Research Group, Justus-Liebig-University, Giessen, Germany.|Department of Neurology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Mesut
authors.initials: M
authors.lastname: Yeniguen
authors.affiliation: Department of Diagnostic and Interventional Radiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Gabriele A
authors.initials: GA
authors.lastname: Krombach
authors.affiliation: Department of Neurology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaps
authors.affiliation: School of Biomedical Sciences & Pharmacy, University of Newcastle, and Hunter Medical Research Institute, Newcastle, NSW, Australia.|Hunter New England Local Health District, New Lambton, NSW, Australia.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Spratt
authors.affiliation: Heart and Brain Research Group, Justus-Liebig-University, Giessen, Germany.|Department of Neurology, Justus-Liebig-University, Giessen, Germany.|Department of Neurology, Buergerhospital Friedberg, Friedberg, Germany.
authors.forename: Tibo
authors.initials: T
authors.lastname: Gerriets
authors.affiliation: Sana Regio Klinkum, Pinneberg, Germany.|Department of Neurology, University Hospital Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Nedelmann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D045423:Microbubbles / Q000627:therapeutic use*; D036103:Nanotechnology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000000981:diagnostic imaging / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D000069453:Ultrasonic Waves; D014463:Ultrasonography; D055114:X-Ray Microtomography