title: Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus.
abstract: Thrombin, a key player in thrombogenesis, affects cells in the brain through activation of its receptors. Low levels of thrombin activity are protective while high levels are toxic. We sought to quantify thrombin activity levels and their spatial distribution in brains of mice following reperfusion after ischemic stroke focusing on infarct, peri-infarct and contralateral areas. In order to find out the contribution of brain-derived thrombin, mRNA levels of both prothrombin and factor X were determined. Furthermore, we assessed the effect of thrombin levels that were measured in the ischemic brain on synaptic transmission. We found that in the brains of mice following transient middle cerebral artery occlusion, thrombin activity is elevated throughout the ischemic hemisphere, including in peri-infarct areas (90 ± 33 and 60 ± 18 mU/mL, in the infarct and peri-infarct areas, respectively, compared to 11 ± 3 and 12 ± 5 mU/mL, in the corresponding contralateral areas; mean ± SE; p < 0.05). Brain mRNA levels of prothrombin and, in particular, factor X are up-regulated in the ischemic core. Hippocampal slices treated with thrombin concentrations as found in the ischemic hemisphere show altered synaptic responses. We conclude that high thrombin activity following reperfusion after ischemic stroke may cause synaptic dysfunction. Following transient middle cerebral artery occlusion in mice, thrombin activity is elevated throughout the ischemic hemisphere, including in peri-infarct areas. Brain mRNA levels of prothrombin and factor X are up-regulated in the ischemic core. Thrombin is known to affect synaptic function in a concentration dependent manner and hippocampal slices treated with the concentrations found in the ischemic hemisphere show altered synaptic responses. We conclude that in ischemic stroke, the high brain thrombin activity found after reperfusion may cause synaptic dysfunction.
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Bushi
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Ben Shimon
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Shavit Stein
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.|Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Robert and Martha Harden Chair in Mental and Neurological Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.|Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Tel Ha Shomer, Israel.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.affiliation: Comprehensive Stroke Center, Department of Neurology and The J. Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel HaShomer, Israel.|Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Tanne
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D020521:Stroke / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013917:Thrombin / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D013917:Thrombin
keywords: PAR1; ischemic stroke; synaptic transmission; thrombin; transient middle cerebral artery occlusion