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[This corrects the article DOI: 10.3389/fphar.2016.00273.].[This corrects the article DOI: 10.3389/fphar.2016.00273.].

During renal ischemia-reperfusion, local and distant tissue injury is caused by an influx of neutrophils into the affected tissues. Here we measured the kinetics of margination and transmigration of neutrophils in vivo in the kidney and lungs following renal ischemia-reperfusion. After bilateral renal injury, kidney neutrophil content increased threefold at 24 h. The neutrophils were found primarily in the interstitium and to a lesser degree marginated to the vascular endothelium. These interstitial neutrophils had significantly lower levels of intracellular IFN-γ, IL-4, IL-6, and IL-10 a tendency for decreased amounts of IL-4 and TNF-α compared to the marginated neutrophils. Localization of the neutrophils to the kidney interstitium was confirmed by high resolution microscopy and these sites of transmigration were directly associated with areas of increased vascular permeability. Activation of the adenosine 2A receptor significantly decreased both kidney neutrophil transmigration by about half and vascular permeability by about a third. After unilateral renal ischemia-reperfusion, the unclipped kidney and lungs did not accumulate interstitial neutrophils or have increased vascular permeability despite a marked increase of neutrophil margination in the lungs. Our findings suggest there is a sequential recruitment and transmigration of neutrophils from the vasculature into the kidney interstitium at the site of tissue injury following renal ischemia-reperfusion.

Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20–25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.

Activation of the adenosine receptor pathway has been demonstrated to be effective in improving tissue remodeling and blunting the inflammatory response. Active colitis is characterized by an intense inflammatory reaction resulting in extensive tissue damage. Symptomatic improvement requires both control of the inflammatory process and repair and remodeling of damaged tissues. We investigated the ability of an A 2A receptor agonist, polydeoxyribonucleotide (PDRN), to restore tissue structural integrity in two experimental colitis models using male Sprague-Dawley rats. In the first model, colitis was induced with a single intra-colonic instillation of dinitrobenzenesulfonic acid (DNBS), 25 mg diluted in 0.8 ml 50% ethanol. After 6 h, animals were randomized to receive either PDRN (8 mg/kg/i.p.), or PDRN + the A 2A antagonist [3,7-dimethyl-1-propargylxanthine (DMPX); 10 mg/kg/i.p.], or vehicle (0.8 ml saline solution) daily. In the second model, dextran sulfate sodium (DSS) was dissolved in drinking water at a concentration of 8%. Control animals received standard drinking water. After 24 h animals were randomized to receive PDRN or PDRN+DMPX as described above. Rats were sacrificed 7 days after receiving DNBS or 5 days after DSS. In both experimental models of colitis, PDRN ameliorated the clinical symptoms and weight loss associated with disease as well as promoted the histological repair of damaged tissues. Moreover, PDRN reduced expression of inflammatory cytokines, myeloperoxidase activity, and malondialdehyde. All these effects were abolished by the concomitant administration of the A 2A antagonist DMPX. Our study suggests that PDRN may represent a promising treatment for improving tissue repair during inflammatory bowel diseases.

Background The blood–brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A 2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A 2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. Methods Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m 2 ). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. Results Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h µg/ml for temozolomide alone and 16.6 ± 2.87 h µg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h µg/ml with temozolomide alone and 3.0 ± 1.7 h µg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and T max in brain were not significantly different. Conclusions Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.

The adenosine A2a receptor agonist CGS21680 has been suggested to act as an anti-inflammatory agent that protects against cardiopulmonary bypass (CPB)-induced organ injury. However, the therapeutic effects of CGS21680 for CPB-induced lung injury have not been comprehensively evaluated. Using a juvenile rat model, the present study was designed to evaluated whether CGS21680 attenuates CPB-induced lung injury. Our juvenile rat CPB model was established by 60 min CPB with or without CGS21680 pretreatment (100 µg/kg, in the CPB priming solution). Rats in the Sham group only underwent cannulation and heparinization. Serum and pulmonary levels of inflammatory markers and histological features of pulmonary tissues were analyzed. All juvenile rats survived following CPB. Significantly elevated serum levels of tumor necrosis factor-α (TNF-α), myeloperoxidase (MPO) and interleukin-1β (IL-1β), and decreased glutathione peroxidase (GSH-PX) levels were observed in the CPB group compared to the Sham group (all P<0.05). TNF-α, MPO and IL-1β were significantly decreased, while GSH-PX was markedly increased in the CGS group when compared to the CPB group. Consistently, pulmonary tissues from rats in the CPB group showed considerable amounts of damaged pneumocytes, severe edema, and increased alveolar macrophages, and significantly higher lung injury scores compared to the controls. Collectively, these changes were all further attenuated by CGS21680. Pretreatment with CGS21680 before CPB attenuated pulmonary injury, which may be related to the anti-inflammatory effects of CGS21680 downstream of A2a receptor activation.

Introduction: The 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug and a major source of substance abuse, which ultimately leads to sensations of well-being, elation and euphoria, moderate derealization/depersonalization, and cognitive disruptions, as well as intense sensory awareness. The mechanisms involved in memory impairment induced by MDMA are not completely understood. Methods: The current study used 40 Sprague-Dawley rats, weighted 200 to 250 g. Experiments were performed in four groups, each containing 10 rats. The first group of rats was used as the control, treated with dimethyl sulfoxide (DMSO). The second group was treated with MDMA. The third group was treated with MDMA and CGS (the adenosine A2A receptor agonist, 2-[p-(2- carboxyethyl) phenethylamino]-5′-N-ethylcarboxamidoadenosine) (CGS 21680) and the fourth group was treated with MDMA and SCH (the A2A receptor antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl-) pyrazolo-[4, 3-e]-1, 2, 4 triazolo [1,5-] pyrimidine]) (SCH 58261). The drugs in all groups were administrated intraperitoneally (i.p.) once a day for 7 days. In 5 rats of each group, following perfusion, samples were taken from hippocampi to investigate apoptosis. Accordingly, the samples were stained using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay kit, and studied by light microscopy. In other rats, fresh tissue was also removed to study the expression of bax and bcl-2 by Western blotting technique. Results: It was observed that the coadministration of MDMA with CGS reduced bax expression and prevented apoptosis of hippocampal cells. The coadministration of MDMA and SCH increased bax expression, and also increased the frequency of hippocampal cell apoptosis. Conclusion: The results of the current study showed that administration of CGS with MDMA decreased the common side effects associated with MDMA.

We assessed the efficacy of a new adenosine A2A agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at 1, 4, and 7 days. Knees in all ATL146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATL146e compared to infected (p < 0.00004) and antibiotics controls (p < 0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL146e groups when compared to infected (p < 0.03) and antibiotics controls (p < 0.05). Addition of an adenosine A2A agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the A2A receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Background Although vasodilator stress myocardial perfusion imaging (MPI) is increasingly performed with exercise, adenosine A 2A receptor agonists have not been studied with exercise. Objectives To determine the safety of administering regadenoson during exercise and, secondarily, to evaluate image quality, patient acceptance, and detection of perfusion defects. Methods Patients requiring pharmacologic MPI received a standard adenosine-supine protocol (AdenoSup, n = 60) and were then randomized (2:1) in a double-blind manner to low-level exercise with bolus intravenous injection of regadenoson (RegEx, n = 39) or placebo (PlcEx, n = 21). Results Adverse events occurred in 95%, 77%, and 33% of patients receiving AdenoSup, RegEx, and PlcEx, respectively. Peak heart rate was 13 beats per minute (bpm) and 21 bpm greater following RegEx compared to that following PlcEx and AdenoSup, respectively ( P  = .006 and <.001). Change from baseline in mean systolic blood pressure (SBP), change from baseline to nadir SBP, and percentage of patients with a decline in SBP by ≥20 mm Hg showed no important differences between RegEx and PlcEx. No occurrences of 2nd degree or higher AV block were observed following RegEx or PlcEx; one patient developed 2nd degree AV block following AdenoSup. The mean heart-to-liver and heart-to-gut ratios were improved on RegEx vs AdenoSup: 0.85 (0.34) vs 0.65 (0.26), P  < .001 and 1.1 (0.36) vs 0.97 (0.34), P  < .001, respectively. Compared to AdenoSup, 70% of patients felt RegEx was much or somewhat better. Conclusions Combining regadenoson with low-level exercise is feasible, well tolerated, and associated with fewer side effects compared to AdenoSup.