Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus.

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.

Bushi D ，Ben Shimon M ，Shavit Stein E ，Chapman J ，Maggio N ，Tanne D ... -  《-》

Pathophysiological dual action of adiponectin after transient focal ischemia in mouse brain.

Yatomi K ，Miyamoto N ，Komine-Kobayashi M ，Liu M ，Oishi H ，Arai H ，Hattori N ，Urabe T ... -  《-》

Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke.

Factor Xa (FXa) plays a critical role in the coagulation cascade by generation of thrombin. During focal ischemia thrombin levels increase in the brain tissue and cause neural damage. This study examined the hypothesis that administration of the FXa inhibitor, apixaban, following focal ischemic stroke may have therapeutic potential by decreasing brain thrombin activity and infarct volume. Male mice were divided into a treated groups that received different doses of apixaban (2, 20, 100 mg/kg administered I.P.) or saline (controls) immediately after blocking the middle cerebral artery (MCA). Thrombin activity was measured by a fluorescence assay on fresh coronal slices taken from the mice brains 24 hr following the MCA occlusion. Infarct volume was assessed using triphenyltetrazolium chloride staining. A high dose of apixaban (100 mg/kg) significantly decreased thrombin activity levels in the ipsilateral hemisphere compared to the control group (Slice#5, p = .016; Slice#6, p = .016; Slice#7, p = .016; Slice#8, p = .036; by the nonparametric Mann-Whitney test). In addition, treatment with apixaban doses of both 100 mg/kg (32 ± 8% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .005 by the nonparametric Mann-Whitney test) and 20 mg/kg (43 ± 7% vs. 76 ± 7% in the treatment vs. control groups respectively; p = .019 by the nonparametric Mann-Whitney test) decreased infarct volumes in areas surrounding the ischemic core (Slices #3 and #8). No brain hemorrhages were observed either in the treated or control groups. In summary, I.P. administration of high dose of apixaban immediately after MCA occlusion decreases brain thrombin activity and reduces infarct size.

Bushi D ，Chapman J ，Wohl A ，Stein ES ，Feingold E ，Tanne D ... -  《-》

Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.

Stein ES ，Itsekson-Hayosh Z ，Aronovich A ，Reisner Y ，Bushi D ，Pick CG ，Tanne D ，Chapman J ，Vlachos A ，Maggio N ... -  《Scientific Reports》

Transient Focal Cerebral Ischemia Leads to miRNA Alterations in Different Brain Regions, Blood Serum, Liver, and Spleen.

Voelz C ，Ebrahimy N ，Zhao W ，Habib P ，Zendedel A ，Pufe T ，Beyer C ，Slowik A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》