Impact of alcohol consumption on the outcome of ischemic stroke and thrombolysis: role of the hepatic clearance of tissue-type plasminogen activator.
OBJECTIVE
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.
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Eloïse
E
Lemarchand
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Maxime
M
Gauberti
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Sara
S
Martinez de Lizarrondo
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Hélène
H
Villain
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Yohann
Y
Repessé
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Axel
A
Montagne
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Denis
D
Vivien
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.).
Carine
C
Ali
From the INSERM UMR-S U919 "serine proteases and pathophysiology of the neurovascular unit" - SP2U Université Caen Basse-Normandie, GIP CYCERON, Caen, France (E.L., M.G., S.M.d.L., H.V., Y.R., A.M., D.V., C.A., M.R.); Service d'Hématologie CHU Caen, France (Y.R.); and Délégation Recherche Clinique et Innovation (DRCI), CHU de Caen, Caen, France (M.R.). rubio@cyceron.fr.
Marina
M
Rubio
D000428:Alcohol Drinking / Q000009:adverse effects* / Q000473:pathology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D051379:Mice; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics* / Q000494:pharmacology
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010959:Tissue Plasminogen Activator
ethanol; fibrinolysis; intravital microscopy