Regadenoson is a selective A2A adenosine receptor agonist with coronary vasodilatory activity[1-2]. Regadenoson functions by selectively activating A2A adenosine receptors, which are predominantly distributed on coronary artery smooth muscle cells. This activation increases adenylate cyclase activity, elevates intracellular cyclic adenosine monophosphate (cAMP) levels, thereby relaxing coronary vessels and significantly augmenting coronary blood flow[3-4].
In vitro, Regadenoson (10µM) was administered to mouse brain endothelial cells (bEnd.3) and rat brain microvascular endothelial cells (RBMEC) for durations ranging from 30 minutes to 4 hours. Treatment with Regadenoson induced cytoskeletal actin filament depolymerization via A2AR activation and downregulated the expression of tight junction proteins (claudin-5, occludin) and adherens junction proteins (VE-cadherin), resulting in a transient disruption of endothelial barrier function[5]. Non-small cell lung cancer cells (A549, H1299) were treated with Regadenoson (5–10µM) for 6 hours. Regadenoson upregulated the expression of the transcription factor Snail via the cAMP/PKA/CREB and PI3K/AKT signaling pathways, thereby inducing epithelial-mesenchymal transition (EMT) [6].
In vivo, K18-hACE2 transgenic mice infected with SARS-CoV-2 received a continuous subcutaneous infusion of Regadenoson (0.5µL/h; 80µg/mL) via an implanted Alzet micro-osmotic pump, initiated prior to infection and sustained for 7 days. Regadenoson significantly improved survival rates and delayed the time to death in the mice[7]. Normal F344 rats received a single intravenous tail vein injection of Regadenoson (0.5µg/kg) administered 60 or 90 minutes after oral temozolomide. Regadenoson significantly increased the concentration of temozolomide in the brain tissue and the brain-to-plasma concentration ratio at the 120-minute time point[8].
References:
[1] Bengalorkar GM, Bhuvana K, Sarala N, et al. Regadenoson. J Postgrad Med. 2012 Apr-Jun;58(2):140-6.
[2] Garnock-Jones KP, Curran MP. Regadenoson. Am J Cardiovasc Drugs. 2010;10(1):65-71.
[3] Ye Z, Sheu WC, Qu H, et al. Autocatalytic, Brain Tumor-Targeting Delivery of Bardoxolone Methyl Self-Assembled Nanoparticles for Glioblastoma Treatment. Small Sci. 2024 May 22;4(8):2400081.
[4] Han L, Cai Q, Tian D, et al. Targeted drug delivery to ischemic stroke via chlorotoxin-anchored, lexiscan-loaded nanoparticles. Nanomedicine. 2016 Oct;12(7):1833-1842.
[5] Vézina A, Manglani M, Morris D, et al. Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model. Mol Cancer Res. 2021 Dec;19(12):2081-2095.
[6] Lu Y, Yang Y, Chang T, et al. Lactate drives CD38 signaling to promote Epithelial-Mesenchymal Transition through Snail induction in non-small cell lung cancer cells. J Cell Commun Signal. 2024 Feb 14;18(1):e12018.
[7] Rabin J, Zhao Y, Mostafa E, et al. Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies. PLoS One. 2023 Aug 11;18(8):e0288920.
[8] Jackson S, Anders NM, Mangraviti A, et al. The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain. J Neurooncol. 2016 Feb;126(3):433-9.
Regadenoson是一种选择性的、具有冠状动脉扩张活性的A2A腺苷受体激动剂[1-2]。Regadenoson通过选择性激活主要分布于冠状动脉平滑肌细胞的A2A腺苷受体，增加腺苷酸环化酶活性，升高细胞内环腺苷酸（cAMP）水平，从而舒张冠状动脉血管，显著增加冠状动脉血流量[3-4]。
在体外，Regadenoson（10μM）处理小鼠脑内皮细胞（bEnd.3）和大鼠脑微血管内皮细胞（RBMEC）30分钟至4小时，Regadenoson通过激活A2AR诱导细胞骨架肌动蛋白丝解聚，并下调紧密连接蛋白（claudin-5、occludin）和黏附连接蛋白（VE-cadherin）的表达，从而瞬时破坏内皮细胞屏障功能[5]。Regadenoson（5–10μM）处理非小细胞肺癌细胞（A549、H1299）6小时，Regadenoson通过cAMP/PKA/CREB和PI3K/AKT信号通路上调转录因子Snail表达，进而诱导上皮-间质转化（EMT）[6]。
在体内，Regadenoson皮下植入Alzet微泵（0.5μL/h；80μg/mL）持续输注处理SARS-CoV-2感染的K18-hACE2转基因小鼠（从感染前开始，持续7天），Regadenoson显著提高小鼠生存率，并延迟死亡时间[7]。Regadenoson（0.5μg/kg）尾静脉注射处理正常F344大鼠（在口服替莫唑胺后60或90分钟单次给药），Regadenoson在120分钟时显著增加脑组织中替莫唑胺浓度和脑组织-血浆浓度比[8]。