Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice
Por:
Garcia-Yebenes, I, Garcia-Culebras, A, Pena-Martinez, C, Fernandez-Lopez, D, Diaz-Guzman, J, Negredo, P, Avendano, C, Castellanos, M, Gasull, T, Davalos, A, Moro, MA and Lizasoain, I
Publicada:
1 sep 2018
Resumen:
Background and Purpose Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy is limited by the risk of hemorrhagic transformation (HT)-the main complication of ischemic stroke. Our aim is to establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent this devastating complication.
Methods-Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration, 4-hydroxynonenal, and matrix metalloproteinase-9 staining).
Results-Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration. Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced serum matrix metalloproteinase-9 increase, and enhanced basal sertun lipid peroxidation. High iron increased brain lipid peroxidation at most times and neutrophil infiltration at the latest time studied.
Conclusions-Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis. Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must be performed to confirm our results.
Filiaciones:
Garcia-Yebenes, I:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Garcia-Culebras, A:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
Pena-Martinez, C:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
Fernandez-Lopez, D:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Diaz-Guzman, J:
Hosp Univ 12 Octubre, Serv Neurol, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
Negredo, P:
Univ Autonoma Madrid, Fac Med, Dept Anat Histol & Neurociencia, Madrid, Spain
Avendano, C:
Univ Autonoma Madrid, Fac Med, Dept Anat Histol & Neurociencia, Madrid, Spain
Castellanos, M:
Complejo Hosp Univ A Coruna, Inst Invest Biomed A Coruna, Serv Neurol, La Coruna, Spain
:
Fundacio Inst Invest Ciencies Salut German Trias, Mol Neurobiol Res Grp, Badalona, Spain
:
Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Dept Neurociencias, Unidad Ictus, Badalona, Spain
Moro, MA:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
Lizasoain, I:
Univ Complutense Madrid, Inst Univ Invest Neuroquim, Unidad Invest Neurovasc, Dept Farmacol & Toxicol,Fac Med, Madrid, Spain
Inst Invest Hosp 12 Octubre I 12, Madrid, Spain
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