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

Abstract

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.

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

“…An accelerating rotarod was used to assess motor deficits [25,43]. Animals were adapted to the rotarod for a period of 3 days before randomization.…”

“…Based on our established protocol [43,46], brain samples were homogenized in TRIzol reagent (Invitrogen, Grand Island, NY, USA). Equal amounts of mRNA were reverse transcribed to cDNA with the PrimeScript RT reagent kit (Thermo Fisher Scientific).…”

An Intersectional Study of LncRNAs and mRNAs Reveals the Potential Therapeutic Targets of Buyang Huanwu Decoction in Experimental Intracerebral Hemorrhage

“…The method was described in Li Q and Wang J [29]. SuperScript III Reverse Transcriptase (Invitrogen, Grand Island, NY, USA) was used to reverse transcribe total RNA into cDNA according to the instructions of the manufacturer.…”

Design and synthesis of nanoscaled IQCA-TAVV as a delivery system capable of antiplatelet activation, targeting arterial thrombus and releasing IQCA

“…19 Through activating the specific membrane receptors for adhesive proteins, the adhesion, activation and aggregation of platelets is triggered at the site of vascular injury to form a plug, that is, thrombus. 20 A series of drugs, such as heparin tissue plasminogen activator, 21,22 urokinase, 23 warfarin 24 and melagatran, 25 have been used to dissolve the formed thrombus or to inhibit the formation of thrombus. On the other hand, these drugs have some clinical shortcomings.…”