Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia

Qiang Li; Xiaoning Han; Xi Lan; Xiaohua Hong; Qian Li; Yufeng Gao; Tianqi Luo; Qingwu Yang; Raymond C. Koehler; Yu Zhai; Jinyuan Zhou; Jian Wang

Neurobiology of Disease (Dec 2017)

Inhibition of tPA-induced hemorrhagic transformation involves adenosine A2b receptor activation after cerebral ischemia

Qiang Li,
Xiaoning Han,
Xi Lan,
Xiaohua Hong,
Qian Li,
Yufeng Gao,
Tianqi Luo,
Qingwu Yang,
Raymond C. Koehler,
Yu Zhai,
Jinyuan Zhou,
Jian Wang

Affiliations

Qiang Li: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Xiaoning Han: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Xi Lan: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Xiaohua Hong: Division of MR Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Qian Li: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Yufeng Gao: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Tianqi Luo: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Qingwu Yang: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
Raymond C. Koehler: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Yu Zhai: Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Correspondence to: Y. Zhai, Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai 200011, China.
Jinyuan Zhou: Division of MR Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Correspondence to: J. Zhou, Division of MR Research, Department of Radiology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Park 336, Baltimore, MD 21287, USA.
Jian Wang: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China; Correspondence to: J. Wang, Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, 720 Rutland Ave, Ross 370B, Baltimore, MD 21205, USA.

Journal volume & issue: Vol. 108
pp. 173 – 182

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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