Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke

Abstract

Background and purpose The debate over the fact that experimental drugs proposed for the treatment of stroke fail in the translation to the clinical situation, has attracted considerable attention in the literature. In this context, we present a retrospective pooled analysis of a large dataset from pre-clinical studies, in order to examine the effects of early versus late administration of intravenous recombinant tissue type plasminogen activator (rt-PA). Methods We collected data from 26 individual studies from 9 international centers (13 researchers, 716 animals) that compared rt-PA to controls, in a unique mouse model of thromboembolic stroke induced by an in situ injection of thrombin into the middle cerebral artery. Studies were classified into early (<3h) versus late (≥3h) drug administration. Final infarct volumes, assessed by histology or MRI, were compared in each study and the absolute differences were pooled in a random-effect meta-analysis. The influence of time of administration was tested. Results When compared to saline controls, early rt-PA administration was associated with a significant benefit (absolute difference = −6.63 mm3; 95%CI, −9.08 to −4.17; I2=76%) whereas late rt-PA treatment showed a deleterious effect (+5.06 mm3; 95%CI, +2.78 to +7.34; I2=42%, Pint<0.00001). Results remained unchanged following subgroup analyses. Conclusion Our results provide the basis needed for the design of future pre-clinical studies on recanalization therapies using this model of thromboembolic stroke in mice. The power analysis reveals that a multi-center trial would require 123 animals per group instead of 40 for a single center trial.

Validation of a stroke model in rat compatible with rt-PA-induced thrombolysis: new hope for successful translation to the clinic

“…Based on this study, many preclinical studies have moved on using a dosage tenfold stronger than what is used in the clinic. The higher dosage of 10 mg/kg is used in the thromboembolic stroke model in mice and has shown similar results that are seen in the clinic 22,23,25 . Studies have also produced irregularities in the efficacy of rt-PA when comparing different dosages in in vivo models 49,50 .…”

“…While previous embolic models have shown variability in clot placements, the clot formed through Orset's model does not move and remains in its original location, generating high reproducibility and low mortality. The model also mimics human ischemic stroke closely by its replication of the thrombi/emboli that gives rise to the blood vessel occlusion in humans; its close clinical resemblance is one of the reasons the model is used by several research groups today [22][23][24][25][26] . With this model's advantages, translation of the model from one species to another would increase the research possibilities by utilizing the benefits from the different species.…”

Early Ultrafast Ultrasound Imaging of Cerebral Perfusion correlates with Ischemic Stroke outcomes and responses to treatment in Mice

“…In this study, the skull was kept intact and image quality was degraded but still enabled quality imaging of cerebral perfusion. Our present work demonstrates in an intact skull setup with a clinically relevant model of Middle Cerebral Artery (MCA) occlusion 23 - 25 that ultrafast Doppler and ULM can provide characterization of cerebral perfusion during an ischemic episode and follow-up in mice. The potential of ULM for transcranial imaging in human patients might allow the imaging of cerebral perfusion very early after stroke onset and possible improvement in medical care.…”

Alcohol exposure–induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages

“…However, the mechanisms mediating this aggravation are not well understood. Our previous results on the impact of alcohol consumption on ischemic stroke, obtained in a clinically relevant thromboembolic model of stroke (9,10), have shown that the aggravating effect of excessive drinking is not due to alcohol-induced changes in hemodynamic Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients.…”