Abstract
BackgroundEarly recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. Microbubble-enhanced sonothrombolysis is a promising therapy to improve recanalization rates and reduce the time to recanalization. Testing any thrombolytic therapy requires a model of thromboembolic stroke, but to date these models have been highly variable with regards to clot stability. Here, we developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA). This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis.MethodsIn Study 1 we investigated spontaneous recanalization rates of PRC in vivo over 4 hours and measured infarct volumes at 24 hours. In Study 2 we investigated tPA-mediated thrombolysis and microbubble-enhanced sonothrombolysis in this model.ResultsStudy 1 demonstrated stable occlusion out to 4 hours in 5 of 7 rats. Two rats spontaneously recanalized at 40 and 70 minutes post-embolism. Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7). In Study 2, recanalization was not observed in any of the groups post-treatment.ConclusionsSite specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction. These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis. This resistance of platelet rich clots to enhanced thrombolysis may explain recanalization failures clinically and should be an impetus to better clot-type identification and alternative recanalization methods.Electronic supplementary materialThe online version of this article (doi:10.1186/s13231-014-0014-y) contains supplementary material, which is available to authorized users.
Highlights
Recanalization of occluded vessels in stroke is closely associated with improved clinical outcome
In study 2 we aimed to investigate the effect on recanalization rates of tissue plasminogen activator (tPA) therapy alone or in conjunction with ultrasound and a new microbubble formulation (BR38) in this model
In Study 2 we investigated the effect of tPA or tPA + ultrasound + BR38 microbubbles compared to saline control in this model (n = 44; performed at JLU)
Summary
Recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. We developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA) This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis. The first clinical report of stroke sonothrombolysis indicated increased rates of recanalization in patients receiving continuous transcranial Doppler ultrasound (TCD) monitoring during tPA therapy [4]. Despite the promise of this therapy, more than half of patients treated do not recanalize [9] and concerns have been raised regarding its Tomkins et al Experimental & Translational Stroke Medicine (2015) 7:2 safety with increased rates of hemorrhage in some studies [6,10]. There is still a great need for pre-clinical studies to better understand the efficacy, mechanisms and safety effects of this potential therapeutic strategy
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