Journal
NEUROBIOLOGY OF DISEASE
Volume 108, Issue -, Pages 173-182Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2017.08.011
Keywords
Adenosine receptor; Cerebral ischemia; tPA; Hemorrhagic transformation
Categories
Funding
- AHA [13GRNT15730001, 17GRNT33660766]
- NIH [K01AG031926, R01NS078026, R01AT007317, R21NS101614, R56NS096549, R01NS083435, R01EB009731, R01NS038684]
- AHA Postdoctoral Fellowship Awards
- Stimulating and Advancing ACCM Research (StAAR) grant from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University
- Innovation Program of Shanghai Municipal Education Commission [14YZ049]
- Shanghai Municipal Natural Science Foundation [17ZR1416200]
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Tissue plasminogen activator (tPA) is administered after ischemic stroke to dissolve intravascular clots, but its use can lead to hemorrhagic transformation (HT). Therapeutic strategies to reduce hemorrhagic complications of tPA might be of benefit for stroke patients. Adenosine A2b receptor (A2bR) plays pivotal roles in regulating vascular protection in peripheral organs. This study explored whether A2bR agonist BAY 60-6583 reduces hemorrhage risk after tPA usage. Using a rat transient middle cerebral artery occlusion model, we showed that mRNA and protein expression of A2bR increased to a greater extent after ischemia-reperfusion than did expression of the other three adenosine receptors (A1, A2a, and A3). tPA administration reduced A2bR expression in ischemic brain microvessels. Post-treatment with BAY 60-6583 (1 mg/kg) at the start of reperfusion reduced lesion volume in the absence or presence of tPA (10 mg/kg) and attenuated brain swelling, blood-brain barrier disruption, and tPA-exacerbated HT at 24 h. Additionally, BAY 60-6583 mitigated sensorimotor deficits in the presence of tPA. BAY 60-6583 inhibited tPA-enhanced matrix metalloprotease-9 activation, probably through elevation of tissue inhibitor of matrix metalloproteinases-1 expression, and thereby reduced degradation of tight junction proteins. These effects would likely protect cerebrovascular integrity. A2bR agonists as an adjuvant to tPA could be a promising strategy for decreasing the risk of HT during treatment for ischemic stroke. (C) 2017 Published by Elsevier Inc.
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