Chronic administration of adenosine A3 receptor agonist and cerebral ischemia: neuronal and glial effects

Lubitz, Dag K.J.E. Von; Lin, Rick C.S.; Boyd, Mellonie; Bischofberger, Norbert; Jacobson, Kenneth A.

doi:10.1016/s0014-2999(98)00977-7

Cited by 57 publications

(36 citation statements)

References 39 publications

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“…In chick ventricular myocyte culture [14] and in the isolated rabbit heart [17], the activation of the A 3 AR showed a preconditioning-like effect that improved the outcome following an ischemic injury. Similar effects were observed in vivo in a gerbil model of global ischemia [8]. In promyelocytic human leukemia HL-60 cells [11], the A 3 AR agonists IB-MECA (l- [6-[[(3-iodophenyl)-methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-β-Dribofuranuronamide) and Cl-IB-MECA induced apoptosis at high concentrations.…”

Section: Introductionsupporting

confidence: 61%

“…Following the introduction of A 3 AR-selective ligands [1][2][3], the A 3 AR has been demonstrated to have diverse physiological functions, including its effects on inflammation [4], hypotension [5], mast cell degradation [6], protection of brain and heart [7][8][9], and apoptosis [10][11][12][13][14][15]. Specifically, potent A 3 AR agonists showed dual effects leading to either cellular protection or death.…”

Section: Introductionmentioning

confidence: 99%

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p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

Kim

Ravi

Hoffmann

et al. 2002

Biochemical Pharmacology

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A 3 adenosine receptor (A 3 AR) agonists have been reported to influence cell death and survival. The effects of an A 3 AR agonist, 1- [2-chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-β-D-ribofuranonamide (Cl-IB-MECA), on apoptosis in two human leukemia cell lines, HL-60 and MOLT-4, were investigated. Cl-IB-MECA (≥30 μM) increased the apoptotic fractions, as determined using fluorescence-activated cell sorting (FACS) analysis, and activated caspase 3 and poly-ADP-ribose-polymerase. Known messengers coupled to A 3 AR (phospholipase C and intracellular calcium) did not seem to play a role in the induction of apoptosis. Neither dantrolene nor BAPTA-AM affected the Cl-IB-MECA-induced apoptosis. Cl-IB-MECA failed to activate phospholipase C in HL-60 cells, while UTP activated it through endogenous P2Y 2 receptors. Induction of apoptosis during a 48 hr exposure to Cl-IB-MECA was not prevented by the A 3 AR antagonists [5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate] (MRS 1220) or N- [9-chloro-2-(2-furanyl) [l,2,4]triazolo [l,5-c]quinazolin-5-yl]benzeneacetamide (MRS 1523). Furthermore, higher concentrations of MRS 1220, which would also antagonize A 1 and A 2A receptors, were ineffective in preventing the apoptosis. Although Cl-IB-MECA has been shown in other systems to cause apoptosis through an A 3 ARmediated mechanism, in these cells it appeared to be an adenosine receptor-independent effect, which required prolonged incubation. In both HL-60 and MOLT-4 cells, Cl-IB-MECA induced the expression of Fas, a death receptor. This induction of Fas was not dependent upon p53, because p53 is not expressed in an active form in either HL-60 or MOLT-4 cells. Cl-IB-MECAinduced apoptosis in HL-60 cells was augmented by an agonistic Fas antibody, CH-11, and this increase was suppressed by the antagonistic anti-Fas antibody ZB-4. Therefore, Cl-IB-MECA induced apoptosis via a novel, p53-independent up-regulation of Fas. Published by Elsevier Science Inc.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

Kim

Ravi

Hoffmann

et al. 2002

Biochemical Pharmacology

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“…Ischemic brain injury in a model of forebrain ischemia in gerbils is reduced upon chronic treatment with 1 [52]. A 3 AR agonist was found to prevent the loss of retinal ganglion cells following activation of the P2×7 receptor in a rat experimental model [53].…”

Section: In Vivo Pharmacological Profile Of A3ar Agonistsmentioning

confidence: 99%

Pharmacological and therapeutic effects of A3 adenosine receptor agonists

Fishman

Bar-Yehuda

Liang

2012

Drug Discovery Today

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The Gi-coupled A3 adenosine receptor (A3AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. The present review summarizes preclinical and clinical human studies demonstrating that A3AR agonists induce specific anti-inflammatory and anticancer effects via a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. Currently, A3AR agonists are being developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.

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“…[12][13][14] The A 3 AR, plays a crucial role in some of the physiological effects of adenosine. 15,16 In addition to cardio- [17][18][19] and cerebroprotective effects, 20,21 hA 3 AR agonists may be therapeutically useful for the treatment of stroke, 22 inflammation 23 and in cancer therapy. 24 While full agonists maximally stimulate the receptor, partial agonists show reduced intrinsic activity, may exhibit fewer side effects 25,26 and may induce less receptor down-regulation and desensitization than full agonists.…”

Section: Introductionmentioning

confidence: 99%

Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety

Rompaey

Jacobson

Gross

et al. 2005

Bioorganic & Medicinal Chemistry

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In this paper we investigated the influence on affinity, selectivity and intrinsic activity upon modification of the adenosine agonist scaffold at the 3′-and 5′-positions of the ribofuranosyl moiety and the 2-and N 6 -positions of the purine base. This resulted in the synthesis of various analogues, that is, 3-12 and 24-33, with good hA 3 AR selectivity and moderate-to-high affinities (as in 32, K i = 27 nM). Interesting was the ability to tune the intrinsic activity depending on the substituent introduced at the 3′-position.

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Chronic administration of adenosine A3 receptor agonist and cerebral ischemia: neuronal and glial effects

Cited by 57 publications

References 39 publications

p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

p53-Independent induction of Fas and apoptosis in leukemic cells by an adenosine derivative, Cl-IB-MECA

Pharmacological and therapeutic effects of A3 adenosine receptor agonists

Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety

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