Sonothrombolysis with BR38 Microbubbles Improves Microvascular Patency in a Rat Model of Stroke

PLoS One. 2016 Apr 14;11(4):e0152898. doi: 10.1371/journal.pone.0152898. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Male
  • Microbubbles / therapeutic use*
  • Nanotechnology
  • Rats
  • Rats, Wistar
  • Stroke / diagnostic imaging
  • Stroke / therapy*
  • Thrombolytic Therapy / methods*
  • Ultrasonic Waves*
  • Ultrasonography
  • X-Ray Microtomography

Grants and funding

Ms. Amelia Tomkins was supported by a Heart Foundation Australia post-graduate scholarship cofounded by the National Stroke Foundation Australia, and by a Hunter Medical Research Institute Travel Scholarship funded by Mrs. Jennie Thomas. Dr. Neil Spratt was supported by an Australian National Health and Medical Research Council Career Development Fellowship (APP1035465). The study was in part supported by Bracco Suisse SA, Geneva, Switzerland and in part from the Faculty of Human Medicine, Justus-Liebig University, Giessen and the German Research Foundation (NST 162/291-1 FUGG). The co-authors, Jean-Marc Hyvelin and Catherine Botteron, are employees of Bracco Suisse SA, Geneva, Switzerland. Their contribution was histology and histological analysis and manuscript preparation in conjunction with all other co-authors. All other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.