Microbubble-mediated sonothrombolysis with BR38 of a venous full blood thrombus in a rat embolic stroke model

Tobias Braun; Laura Sünner; Maaike Hachenberger; Clemens Müller; Astrid Wietelmann; Martin Juenemann; Jörn Pons-Kühnemann; Manfred Kaps; Tibo Gerriets; Marlene Tschernatsch; Joachim Roth; Mesut Yenigün

doi:10.21037/atm-21-75

Microbubble-mediated sonothrombolysis with BR38 of a venous full blood thrombus in a rat embolic stroke model

Ann Transl Med. 2021 Jul;9(13):1061. doi: 10.21037/atm-21-75.

Authors

Tobias Braun^{1

2}, Laura Sünner², Maaike Hachenberger^{1

2}, Clemens Müller³, Astrid Wietelmann⁴, Martin Juenemann^{1

2}, Jörn Pons-Kühnemann⁵, Manfred Kaps¹, Tibo Gerriets^{1

2

6}, Marlene Tschernatsch^{1

2

6}, Joachim Roth⁷, Mesut Yenigün^{1

2}

Affiliations

¹ Department of Neurology, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany.
² Heart & Brain Research Group, Justus-Liebig-University Giessen and Kerckhoff Clinic, Bad Nauheim, Germany.
³ Department of Radiology, Kerckhoff Clinic, Bad Nauheim, Germany.
⁴ Scientific Service Group Magnetic Resonance Imaging, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
⁵ Institute of Medical Informatics, Department of Medical Statistics, Justus-Liebig-University, Giessen, Germany.
⁶ Department of Neurology, Gesundheitszentrum Wetterau, Bad Nauheim, Germany.
⁷ Department of Veterinarian Physiology and Biochemistry, Justus-Liebig-University, Giessen, Germany.

Abstract

Background: Early recanalization of an occluded vessel is associated with a better clinical outcome in acute ischemic stroke. Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only available in a minority of patients and often fails to reopen the occluded vessel. Mechanical recanalization is more effective in this matter but only available for selected patients when a thrombectomy centre can be reached. Therefore, sonothrombolysis might represent an alternative or complementary approach. Here, we tested microbubble-mediated sonothrombolysis (mmSTL) in a thromboembolic stroke model for middle cerebral artery occlusion (MCAO) in rats.

Methods: Sixty-seven male Wistar rats underwent MCAO using an autologous full blood thrombus and were randomly assigned to four groups receiving rt-PA, mmSTL, a combination of both, or a placebo. Diagnostic workup included neurological examination, assessment of infarct size, and presence of intracerebral haemorrhage by magnetic resonance imaging (MRI) and presence of microbleedings in histological staining.

Results: Neurological examination revealed no differences between the treatment groups. In all treatment groups, there was a reduction in infarct size 24 hours after MCAO as compared to the placebo (P≤0.05), but there were no differences between the active treatment groups (P>0.05) (placebo 0.75±0.10 cm³; mmSTL 0.43±0.07 cm³; rt-PA 0.4±0.07 cm³; mmSTL + rt-PA 0.27±0.08 cm³). Histological staining displayed intracerebral microbleedings in all animals. The frequency of gross bleeding detected by MRI did not differ between the groups (placebo 3; mmSTL 4; rt-PA 2; mmSTL + rt-PA 2; P>0.05) and was not associated with worse performance in clinical testing (P>0.05). There were no statistical differences in the mortality between the groups (P>0.05).

Conclusions: Our study showed the efficacy and safety of mmSTL with or without rt-PA in an embolic rat stroke model using a continuous full blood thrombus. Sonothrombolysis might be useful for patients who need to be transported to a thrombectomy centre or for those with distal vessel occlusion.

Keywords: Embolic stroke; microbubbles; rat; sonothrombolysis; ultrasound (US).