scholarly journals Adenosine Receptors and Wound Healing, Revised

2006 ◽  
Vol 6 ◽  
pp. 984-991 ◽  
Author(s):  
Bruce M. Cronstein
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Inflammatory Cells ◽  
Diabetic Foot Ulcers ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
A2a Receptor ◽  
Adenosine Agonists ◽  
Healing Wounds ◽  
Adenosine A2a

Recent studies have demonstrated that application of topical adenosine A2A receptor agonists promotes more rapid wound closure and clinical studies are currently underway to determine the utility of topical A2Aadenosine receptor agonists in the therapy of diabetic foot ulcers. The effects of adenosine A2Areceptors on the cells and tissues of healing wounds have only recently been explored. Here we summarize the evidence indicating that adenosine and selective adenosine agonists, acting at A2Areceptors, promote the salutary functions of inflammatory cells, endothelial cells and fibroblasts in stimulating wound healing.

scholarly journals Adenosine Receptors and Wound Healing

2004 ◽  
Vol 4 ◽  
pp. 1-8 ◽  
Author(s):  
Bruce N. Cronstein
Keyword(s):  
Wound Healing ◽  
Adenosine Receptors ◽  
Diabetic Foot ◽  
Wound Closure ◽  
Receptor Occupancy ◽  
Foot Ulcers ◽  
Diabetic Foot Ulcers ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Healing Wounds

Recent studies have demonstrated that application of topical adenosine A2Areceptor agonists promotes more rapid wound closure and clinical studies are currently underway to determine the utility of topical A2Aadenosine receptor agonists in the therapy of diabetic foot ulcers. The effects of adenosine A2Areceptors on the cells and tissues of healing wounds have only recently been explored. We review here the known effects of adenosine A2Areceptor occupancy on the cells involved in wound healing.

Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 593-602 ◽  
Author(s):  
Richard J. Rickles ◽  
Laura T. Pierce ◽  
Thomas P. Giordano ◽  
Winnie F. Tam ◽  
Douglas W. McMillin ◽  
...  
Keyword(s):  
B Cell ◽  
Adenosine Receptor ◽  
High Throughput Screening ◽  
B Cell Lymphoma ◽  
Adenosine A2a Receptor ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Pde Inhibitors ◽  
A2a Receptor ◽  
Adenosine A2a

Abstract Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B. We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations.

Adenosine A2A Receptor Agonism and PDE Inhibition: A Synergistic Multi-Target Mechanism Discovered through Systematic Combination Screening in Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 847-847
Author(s):  
Richard J Rickles ◽  
Laura Pierce ◽  
Thomas Giordano ◽  
Winnie F. Tam ◽  
Douglas W. McMillin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Adenosine Receptor ◽  
Adenosine A2a Receptor ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Pde Inhibitors ◽  
A2a Receptor ◽  
Pde Inhibition ◽  
Adenosine A2a

Abstract Using a combination high throughput screening technology, we have discovered an unexpected synergistic interaction between adenosine A2A receptor (A2A) agonism and phosphodiesterase (PDE) inhibition that displays substantial activity in preclinical Multiple Myeloma (MM) models. High throughput combination screening allows the systematic testing of combinations of approved drugs and other biologically active molecules in cell based assays of tumor cell proliferation and viability. In this approach we generate a dose matrix for each chemical combination, capturing the combined activity of two compounds over a broad range of single agent concentrations. Quantitative scoring of dose response matrices using models of drug interactions allows insight into the biological mechanism of action of drug combinations and the discovery of novel therapeutic applications. Using a panel of 4 MM cell lines (H929, MM.1S, MM.1R and RPMI-8226) we evaluated a defined set of combinations of approved drugs and molecular probes. A total of 2841 unique combinations were evaluated, 648 of which were assayed in all 4 cell lines. Multiple combinations were identified that exceeded the Loewe additivity model including enhancers of known anti-cancer drugs and combinations of targets not previously know in multiple myeloma. Multiple classes of drugs and targeted agents were identified that synergize with dexamethasone. Backcrosses of these active agents revealed multiple dexamethasone enhancers that also synergized with each other. Two of these classes, A2A agonists and PDE inhibitors demonstrated high levels of synergy and good breadth of activity across several MM cell lines. Interestingly, while the majority of the combinations screened had little or no synergistic effect in the glucocorticoid resistant MM.1R cell line, combinations of PDE inhibitors and A2A agonists demonstrated substantial efficacy (>90% inhibition of proliferation) and striking synergy (combination indices<0.3) in this cell line. We have used panels of selective adenosine receptor agonists, antagonists and PDE inhibitors as well as siRNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. All adenosine receptor agonists tested synergize with the multi-PDE isoform inhibitor trequinsin. Synergy between the A2A agonist Chloro-IB-MECA and trequinsin is suppressed by the adenosine A2A antagonist SCH58261 at 78 nM but not by the A1, A2B or A3 antagonists DPCPX, MRS1754 and MRS1523 respectively, demonstrating that A2A agonism is the necessary component of the synergistic multi-target mechanism. Furthermore, siRNA knockdown of adenosine A2A but not A1, A2B or A3 receptors blocks the activity of all adenosine receptor agonists examined. Similarly, using 22 subtype specific PDE inhibitors, we find that the specific subset of PDE2, 3, 4 and 7, are able to synergize with A2A agonists. By combining subtype inhibitors and/or siRNAs targeting specific PDE isoforms we find that maximal activity is observed when more than one PDE is targeted. Inhibition of both PDE3 and 4 results in the greatest synergy, with further enhancement from the addition of PDE2 and/or PDE7 inhibition. During treatment with A2A agonists and PDE inhibitors there is a compensatory 13-fold up-regulation of PDE4B, as measured by qPCR, suggesting that inhibition of this isoform is particularly important for maximal antiproliferative activity. We find that neither A2A agonism nor PDE inhibition alone induces cAMP accumulation in MM cell lines. However, the combination of A2A activation and PDE inhibition leads to elevated intracellular cAMP and cell death. Notably, the activity of A2A agonists is enhanced in the presence of 10 ng/mL interleukin-6 and HS-5 human bone marrow stromal cells and the synergy between A2A agonists and PDE inhibitors is preserved under these conditions. In summary, we describe the use of cHTS screening to discover new synergistic multi-target mechanisms and prioritize synergistic anti-proliferative combinations for preclinical evaluation. This approach has resulted in the discovery of adenosine A2A receptor agonism and PDE inhibition as a highly selective and synergistic multi-target mechanism with therapeutic potential in MM.

A2A Adenosine Receptor Agonists and their Potential Therapeutic Applications. An Update

2018 ◽  
Vol 25 (30) ◽  
pp. 3597-3612 ◽  
Author(s):  
Angel Guerrero
Keyword(s):  
Wound Healing ◽  
Reperfusion Injury ◽  
Adenosine Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
A2a Adenosine Receptor Agonists ◽  
Adenosine Receptor Agonists ◽  
Therapeutic Applications ◽  
Receptor Agonists ◽  
A2a Receptor

Background: Adenosine is an endogenous purine nucleoside, which mediates a variety of important biological processes and diseases, such as vasodilation, inflammation, cancer, wound healing, ischemia reperfusion injury, Parkinson disease, infectious diseases, and other CNS disorders. Particularly important are the A2A receptors that have been expressed in the lung, liver, heart, cardiovascular tissues, leukocytes, neutrophils, and endothelial cells. This review provides an update of the latest A2A receptor agonists developed in the period 2005-2017, their selectivity regarding other adenosine receptors and their potential therapeutic applications. Methods: I have conducted an extensive search from the most common bibliographic databases for critically review the most recent works on the A2A receptor agonists and their therapeutic applications in inflammation, asthma and chronic obstructive pulmonary disease, myocardial perfusion imaging, sepsis, rheumatoid arthritis, and wound healing, among others. Results: In the last decade, a great deal of effort has been devoted to develop adenosine receptor agonists and antagonists for treatment of a number of diseases. Thus, for A2A receptor agonists more than 130 papers and reviews have been found, many of them highlighting the usefulness of these compounds in the field. Conclusions: Although so far many of the A2A receptor agonists have failed in clinical trials due to their side effects, some of them have been approved for protection against cardiac ischemia-reperfusion injury and anemia. The recently reported crystal structure of the human A2A receptor in complex with the agonist UK-432097 is a fundamental keystone for the development of new and selective A2A ligands with new therapeutic applications.

scholarly journals The Diameter of Retinal Arterioles Is Unaffected by Intravascular Administration of the Adenosine A2A Receptor Agonist Regadenoson in Normal Persons

2019 ◽  
Vol 4 (2) ◽  
pp. 1-10 ◽  
Author(s):  
Anna Dons-Jensen ◽  
Line Petersen ◽  
Hans-Erik Bøtker ◽  
Toke Bek
Keyword(s):  
Intravenous Administration ◽  
Receptor Agonist ◽  
Adenosine A2a Receptor ◽  
Retinal Vessels ◽  
Adenosine Receptor Agonists ◽  
Retinal Arterioles ◽  
A2a Receptor ◽  
Adenosine A2a

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

scholarly journals Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time

2012 ◽  
Vol 166 (6) ◽  
pp. 1846-1859 ◽  
Author(s):  
Dong Guo ◽  
Thea Mulder-Krieger ◽  
Adriaan P IJzerman ◽  
Laura H Heitman
Keyword(s):  
Residence Time ◽  
Adenosine A2a Receptor ◽  
Receptor Agonists ◽  
A2a Receptor ◽  
Adenosine A2a

scholarly journals Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

2017 ◽  
Vol 25 (1-2) ◽  
pp. 21-29
Author(s):  
Mirosław Jasiński ◽  
Magdalena Chrościńska-Krawczyk ◽  
Stanisław J. Czuczwar
Keyword(s):  
Adenosine Receptor ◽  
Anticonvulsant Activity ◽  
Pharmacokinetic Interaction ◽  
Maximal Electroshock ◽  
Protective Activity ◽  
Adenosine Receptor Agonists ◽  
Brain Concentration ◽  
Receptor Agonists ◽  
Adenosine Agonists ◽  
Free Plasma

SummaryBackground.Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.Aim.To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.Methods.The following adenosine receptor agonists were used: A1– cyclohexyladenosine, A2A– CGS 21 680, A3– N6-benzyl-NECA and A1(preferentially) and A2– 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1and A2antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.Results.Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).Conclusion.The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.

Association of Non-Healing Wounds, Pain and Neurochemical Alterations In Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 842-842
Author(s):  
Josephine Anuforo ◽  
Julia Nguyen ◽  
Kathryn Luk ◽  
Silas Wallen-Friedman ◽  
Divyanshoo Kohli ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Wound Healing ◽  
Neurogenic Inflammation ◽  
Wound Closure ◽  
Thermal Hyperalgesia ◽  
Nerve Fibers ◽  
Primary Afferents ◽  
Leg Ulcers ◽  
Cell Disease ◽  
Healing Wounds

Abstract Abstract 842 The mechanisms underlying non-healing leg ulcers in sickle cell disease (SCD) remain unknown and their treatment is difficult. We hypothesized that leg ulcers in SCD cause injury to nerve fibers leading to neurogenic inflammation, and peripheral and central sensitization resulting in chronic pain and impairment of wound healing. We examined our hypotheses by creating 4 mm punch biopsies on the lower thigh of the left leg (LL) of 12 wk old BERK and hemizygous BERK (hBERK) mice expressing sickle hemoglobin (HbS). Since BERK did not survive wounding, hBERK and control HbA-BERK, expressing normal human HbA and wild type C57/BL6, were used. hBERK appeared to be a suitable model for this study because we found that >5 mo old BERK and hBERK show deep tissue and cutaneous hyperalgesia similar to pain in human SCD (Blood 116:456-65, 2010). Wounds were treated with topical morphine (3 mg/g Eucerin base cream) or with Eucerin base cream twice a day. Behavioral measures of hyperalgesia were assessed by paw withdrawal frequency (PWF) per 10 applications of a 1.0 g von Frey monofilament and paw withdrawal latency (PWL) in response to a radiant heat stimulus, applied to the plantar surface of the hind paw of wounded left leg and unwounded right leg. No hyperalgesia was observed in 12 wk old hBERK (baseline), but wounding led to a sharp increase in PWF and decrease in PWL, in LL for 24h, suggestive of wound-induced pain. Topical application of morphine significantly decreased mechanical and thermal hyperalgesia after 1h and 24h as compared to the base cream treated wound (p<0.05) in LL. Pain measures returned to baseline 2 wks post-wounding in morphine- but base cream-treated hBERK mice exhibited hyperalgesia for 4 wks (last measurement). The right leg exhibited increased mechanical but not thermal hyperalgesia following the wounding of left leg in hBERK. HbA-BERK and C57/BL6 wounds treated with base cream showed an increase in pain which was significantly less than hBERK and reached baseline 2 wks post-wounding, suggesting that wounding results in chronic pain in hBERK mice. Increased pain was accompanied by decreased wound closure in hBERK mice. Morphine-treated mice showed 100% wound closure at 4d Vs 8d in base cream treated hBERK, indicative of morphine-induced augmentation of wound healing. Laser scanning confocal microscopy (LSCM) of whole dorsal root ganglion (DRG) showed that, activating transcription factor 3 (ATF3), a marker of neuronal injury, was highly expressed in left lumbar DRG of base cream Vs morphine treated wounded hBERK, 30d post-wounding (p<0.05), suggestive of ongoing wound-induced neuronal injury which is abrogated by topical morphine. LSCM of 100 micron thick sections of healed wounds showed that substance P (SP), a neuropeptide expressed in nociceptive primary afferents, was significantly increased in base cream treated Vs morphine treated healed wounds 30d post wounding (p<0.01). Increased SP was accompanied by reduced and disorganized protein gene product (PGP 9.5)-ir nerve fibers and vasculature in base cream treated wounds. In contrast, morphine treated wounds showed normally organized dense PGP 9.5-ir nerve fibers and blood vessels replete with nerve and vascular plexus similar to their presentation in normal skin. Together, these data show that wounds stimulate chronic pain accompanied by nerve injury, central sensitization and neurogenic inflammation; and that morphine ameliorates this noxious insult and promotes wound healing. In addition, morphine may directly influence wound healing by promoting angiogenesis. It is possible that chronic pain may contribute to impaired wound healing and that non-healing wounds contribute to chronic pain in SCD. We propose that wound-induced nerve signal conduction (ATF3 in DRG) and neurogenic inflammation/sensitization of primary afferents (SP in skin) may contribute to chronic pain and in turn interfere with wound healing. Our observations suggest that neurochemical and behavioral alterations orchestrated by wounding may contribute to the impairment of healing of leg ulcers in SCD. We speculate that topical application of morphine may ameliorate pain and promote healing of painful leg ulcers in SCD. Disclosures: No relevant conflicts of interest to declare.

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