Attenuation of experimental subarachnoid hemorrhage–induced cerebral vasospasm by the adenosine A2A receptor agonist CGS 21680

Lin, Chih‐Lung; Shih, Huei-Chuan; Lieu, Ann-Shung; Lee, Kung-Shing; Dumont, Aaron S.; Kassell, Neal F.; Howng, Shen-Long; Kwan, Aij‐Lie

doi:10.3171/jns.2007.106.3.436

Cited by 22 publications

(20 citation statements)

References 51 publications

(66 reference statements)

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“…Park et al also observed a reduction in eNOS protein in rats with SAH [26]. Recently, the eNOS-based therapeutics held the therapeutic promise in the treatment of cerebral vasospasm following SAH [21,27,28]. Our results revealed that AG treatment via the inhibition of iNOS activity significant reversed the decreased levels of eNOS mRNA and protein, and consequently ameliorating the cerebral vasospasm after the induction of SAH.…”

Section: Discussionsupporting

confidence: 58%

Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells

Zheng

Wang

et al. 2010

Journal of the Neurological Sciences

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Section: Discussionsupporting

confidence: 58%

Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells

Zheng

Wang

et al. 2010

Journal of the Neurological Sciences

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“…A 2A AR mediated NO release is also well recognized in various endothelial cell culture studies, including human, rat and porcine [4,34,35]. In another study [36], the authors stated that L-NAME abrogates 1 nM CGS-21680 dilatory response in Langendorff mouse heart.…”

Section: Discussionmentioning

confidence: 87%

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

Teng¹,

Ledent²,

Mustafa³

2008

Journal of Molecular and Cellular Cardiology

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In this study, we looked into possible compensatory changes of other adenosine receptors (AR) in A 2A genetic knockout mice (A2AKO) as well as the functional role of nitric oxide (NO) in A 2A ARmediated vasodilation. Gene expression of ARs from coronary arteries of A 2A AR wild type mice (A2AWT) and A2AKO were studied using real time-PCR. Functional studies were carried out in isolated heart and isolated coronary artery preparations. A 2B AR was found to be 4.5 fold higher in A2AKO than in A2AWT, while A 2A AR expression was absent in A2AKO. There was no difference in A 1 and A 3 ARs between WT and KO animals. The concentration-relaxation curve for adenosine-5′-N-ethylcarboxamide (NECA, non-selective AR agonist) in isolated coronary arterial rings in A2AKO was shifted to the left when compared to A2AWT. The concentration-response curve for A 2B selective agonist (Bay 60-6583) was also shifted to the left in A2AKO hearts. L-NAME, a nonspecific NO synthase inhibitor, did not affect baseline coronary flow (CF) until the concentration reached 10 µM in A 2A WT (76.32 ± 11.35% from baseline, n=5). In A 2A KO, the CF decreased significantly by L-NAME only at a higher concentration (100 µM, 93.32 ± 5.8% from baseline, n=5). L-NMA (1 µM, n=4), another non-specific NO synthase inhibitor, also demonstrated similar results in decreasing CF (59.66±3.23% from baseline in A2AWT, while 81.76±8.91% in A2AKO). It was further demonstrated that the increase in CF by 100 µM NECA was significantly blunted with 10 µM L-NAME (377.08 ± 25.23% to 305.41 ± 30.73%, n=9) in A 2A WT but not in A 2A KO (153.66 ± 22.7% to 143.88 ± 36.65%, n=5). Similar results were also found using 50 nM of CGS-21680 instead of NECA in A 2A WT (346±22.85 to 277±31.39, n=6). No change in CF to CGS-21680 was noted in A 2A AKO. Our data demonstrate, for the first time, that coronary A 2B AR was up-regulated in mice deficient in A 2A AR. We also provide direct evidence supporting a role for NO in A 2A AR-mediated coronary vasodilation. The data further support the role for A 2A AR in the regulation of basal coronary tone through the release of NO.

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“…The role of JNK MAPK may well be crucial to cell survival and regeneration in SCI and may represent a target for pharmacological tools aimed at improving neuron recovery. Lin et al (12) demonstrated that the A 2A agonist ATL 202 rapidly and persistently reduces locomotor dysfunction and SC demyelination after SCI. Therefore, a reducing effect of JNK in oligodendrocytes might contribute to the protective effect of the A 2A selective agonist CGS 21680 against SCI-induced demyelination.…”

Section: Discussionmentioning

confidence: 98%

“…Most studies report that selective activation of A 2A receptors inhibits proinflammatory responses in bone marrowYderived cells, including platelets, monocytes, some mast cells, neutrophils, and T cells (10,11). The work of Lin et al (12) in chimeric mice selectively lacking bone marrow A 2A receptors demonstrates that inflammatory bone marrowYderived cells are the primary targets of A 2A agonistYmediated protection from SCI. In in vivo models of SCI, A 2A agonism proved protective against different inflammatory readouts (6,13,14).…”

Section: Introductionmentioning

confidence: 97%

The Selective Adenosine A2a Receptor Agonist CGS 21680 Reduces JNK Mapk Activation in Oligodendrocytes in Injured Spinal Cord

Genovese¹,

Melani²,

Esposito³

et al. 2009

Shock

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Permanent functional deficit after spinal cord injury (SCI) arises from both mechanical injury and from secondary tissue reactions involving inflammation. Adenosine is an important regulator of inflammatory mechanisms. Although functional studies indicate a protective effect of adenosine A2A receptor agonists in SCI, the basic molecular mechanisms accounting for the their protective effects from SCI have to be fully elucidated. In this study, we investigated if the selective A2A receptor agonist 2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) administered after SCI has protective effects against tissue damage, motor deficit, and different inflammatory readouts. Spinal cord injury was induced in mice by extradural compression of a section of the SC exposed via a four-level T5-T8 laminectomy. CGS 21680, administered by subcutaneously implanted osmotic minipumps after SCI, clearly reduced motor deficit for up to 19 days after operation. The drug repeatedly administered intraperitoneally after SCI reduced tissue damage, influx of myeloperoxidase-positive leukocytes, nuclear factor-kappaB activation and iNOS expression in injured spinal cord tissue 24 h after SCI. Enhanced immunoreactivity of microglia, astrocytes, and oligodendrocytes (stained by anti-CD11/B, anti-glial fibrillary acidic protein, and anti-Olig2 antibodies, respectively) was also observed 24 h after SCI. Neurons lose immunoreactivity in the nucleus. c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase, quantified by Western blot, was definitely activated in injured tissue. CGS 21680 treatment significantly reduced JNK phosporylation. Phospho-JNK mitogen-activated protein kinase was de novo expressed selectively in oligodendrocytes. CGS 21680 reduced phospho-JNK immunostaining in oligodendrocytes. Data indicate that protection by the A2A agonist is secondary to reduced leukocyte recruitment in the damaged area. A reducing effect of JNK activation in oligodendrocytes might account for protective effect of the A2A agonist against SCI-induced demyelination.

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Attenuation of experimental subarachnoid hemorrhage–induced cerebral vasospasm by the adenosine A2A receptor agonist CGS 21680

Cited by 22 publications

References 51 publications

Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells

Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells

Up-regulation of A2B adenosine receptor in A2A adenosine receptor knockout mouse coronary artery

The Selective Adenosine A2a Receptor Agonist CGS 21680 Reduces JNK Mapk Activation in Oligodendrocytes in Injured Spinal Cord

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