Protective Effects of Adenosine Receptor Agonist in a Cirrhotic Liver Resection Model

Iskandarov, Emil; Srinivasan, Pramod Kadaba; Wang, Xin; Berne, Christian; Afify, Mohamed; Hamza, Astrit; Wei, Lai; Hata, Koichiro; Agayev, Boyukkishi; Tolba, René

doi:10.5812/hepatmon.36821

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…A 1 R antagonists abolished ischaemic preconditioning. After the resection of bile-duct-ligated cirrhotic livers, an A 2A R agonist improved liver function ( Iskandarov et al, 2016 ). Inhalation of high concentrations of hydrogen protects against ischaemia/reperfusion injury through A 2A R activation ( Li H. et al, 2017 ).…”

Section: Diseases Of the Livermentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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Section: Diseases Of the Livermentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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“…Notably, in mice liver transplantation, A2A receptor activation attenuates an inflammatory response by blocking NF‐κB activation in grafts, thereby reducing apoptosis and improving the survival of liver grafts (L. M. Tang et al, 2010). Moreover, in the cirrhotic liver resection model, activation of the A2A receptor significantly improves liver function, regeneration, and microcirculation, providing robust protection against inflammation and apoptosis (Iskandarov et al, 2016). Interestingly, in wild‐type mice, adenosine receptor A2B signaling also inhibits NF‐κB activation, providing a unique role in liver protection during IRI, but not in A2BR −/− mice (Smith, 2013).…”

Section: The Protective Effect Of the Cd39–cd73–adenosine Pathway In mentioning

confidence: 99%

The role of the CD39–CD73–adenosine pathway in liver disease

Wang

Gao

Zhou

et al. 2020

Journal Cellular Physiology

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Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5′-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.

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“…Selective A2a receptor agonist CGS 21680 (Sigma Chemicals, Saint Louis, MO, USA) was added to the last 250 mL of the HTK solution (0.005 mg/mL). The dosage for the CGS 21680 was modified for a large animal setting from previous studies by our group and by others [ 17 , 49 , 60 ].…”

Section: Methodsmentioning

confidence: 99%

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

Czigány

Craigie

Lurje

et al. 2020

IJMS

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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.

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Protective Effects of Adenosine Receptor Agonist in a Cirrhotic Liver Resection Model

Cited by 6 publications

References 35 publications

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling: Therapeutic Developments

The role of the CD39–CD73–adenosine pathway in liver disease

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

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