BACKGROUND AND PURPOSE: Tissue-type plasminogen activator (tPA) is the only acute treatment for ischemic stroke. Unfortunately, the benefit of tPA-driven thrombolysis is not systematic, and understanding the reasons for this is mandatory. The balance between beneficial and detrimental effects of tPA might explain the limited overall efficiency of thrombolysis. Here, we investigated whether this balance could be influenced by excessive alcohol intake.
METHODS: We used a murine model of thromboembolic stroke, coupled to an array of biochemical assays, near-infrared or magnetic resonance imaging scans, 2-photon microscopy, hydrodynamic transfections, and immunohistological techniques.
RESULTS: We found that 6 weeks of alcohol consumption (10% in drinking water) worsens ischemic lesions and cancels the beneficial effects of tPA-induced thrombolysis. We accumulate in vivo and in vitro evidence showing that this aggravation is correlated with a decrease in lipoprotein receptor-related protein 1-mediated hepatic clearance of tPA in alcohol-exposed mice.
CONCLUSIONS: An efficient liver-driven clearance of tPA might influence the safety of thrombolysis after stroke.
- Alcohol Drinking/adverse effects
- Brain Ischemia/drug therapy
- Disease Models, Animal
- Low Density Lipoprotein Receptor-Related Protein-1/metabolism
- Stroke/drug therapy
- Thrombolytic Therapy
- Tissue Plasminogen Activator/pharmacokinetics