RT Journal Article
SR Electronic
T1 Thrombin Activity Associated with Neuronal Damage during Acute Focal Ischemia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7622
OP 7631
DO 10.1523/JNEUROSCI.0369-12.2012
VO 32
IS 22
A1 Bo Chen
A1 Beth Friedman
A1 Michael A. Whitney
A1 Jessica A. Van Winkle
A1 I-Farn Lei
A1 Emilia S. Olson
A1 Qun Cheng
A1 Benedict Pereira
A1 Lifu Zhao
A1 Roger Y. Tsien
A1 Patrick D. Lyden
YR 2012
UL http://www.jneurosci.org/content/32/22/7622.abstract
AB Mechanisms of ischemic neuronal and vascular injury remain obscure. Here we test the hypothesis that thrombin, a blood-borne coagulation factor, contributes to neurovascular injury during acute focal ischemia. Stroke was induced in adult Sprague Dawley rats by occluding the middle cerebral artery. Intra-arterial thrombin infusion during ischemia significantly increased vascular disruption and cellular injury. Intravenous infusion of argatroban, a direct thrombin inhibitor, alleviated neurovascular injury. Immunostaining showed thrombin on neurons in the ischemic core. Using an activatable cell-penetrating peptide engineered to detect thrombin activity, we discovered that thrombin proteolytic activity was specifically associated with neuronal damage during ischemia. Protease activated receptor-1, the presumptive thrombin receptor, appeared to mediate ischemic neurovascular injury. Furthermore, rats receiving thrombin during ischemia showed cognitive deficit, whereas rats receiving argatroban retained intact learning and memory. These results suggest a potential role for thrombin contributing to neurovascular injury and several potential avenues for neuroprotection.