Enhanced airway reactivity and inflammation in A<sub>2A</sub>adenosine receptor-deficient allergic mice

Nadeem, Ahmed; Fan, Min; Ansari, Hena A; Ledent, Catherine; Mustafa, S. Jamal

doi:10.1152/ajplung.00416.2006

Cited by 55 publications

(55 citation statements)

References 44 publications

(65 reference statements)

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“…Total RNA was isolated from amygdala and hypothalamus using the TRIzol reagent (Invitrogen) followed by DNase treatment to eliminate potential genomic DNA contamination as described by Nadeem et al (2007). This was followed by conversion of 0.5 g of total RNA into cDNA using the High Capacity cDNA archive kit (Applied Biosystems, Foster City, CA) in a total volume of 100 l. Real-time PCR was performed on an ABI PRISM 7300 Detection System (Applied Biosystems) using TaqMan Universal Mastermix (Applied Biosystems).…”

Section: Biochemical and Molecular Assaysmentioning

confidence: 99%

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Masood

Nadeem²,

Mustafa³

et al. 2008

J Pharmacol Exp Ther

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199

168

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The pathogenesis of several neuropsychiatric disorders, including anxiety and depression, has been linked to oxidative stress, in part via alterations in cyclic nucleotide signaling. Phosphodiesterase-2 (PDE2), which regulates cGMP and cAMP signaling, may affect anxiety-related behavior through reduction of oxidative stress. The present study evaluated the effects of oxidative stress on behavior and assessed the anxiolytic effects of the PDE2 inhibitor Bay 60-7550 [(2-(3,4-Treatment of mice with L-buthionine-(S,R)-sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plusmaze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 60-7550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.Anxiety and fear are normal emotional responses to threatening stimuli. These responses are abnormal in human anxiety disorders, such as panic disorder, post-traumatic stress disorder, social phobias, and generalized anxiety disorder. The development of anxiety/stress-related disorders involves complex interactions among various body mechanisms involving the limbic system and the hypothalamic-pituitaryadrenal axis; their interactions play a significant role in the manifestation of disease pathology (Chrousos and Gold, 1992;Ray et al., 1993). Exposure to stressful stimuli produces widespread physiological and behavioral effects in animals. In recent studies, oxidative stress has been shown to be associated with anxiety in different behavioral models (Gingrich, 2005;Hovatta et al., 2005;Berry et al., 2007).The nervous system, due to enriched concentrations of polyunsaturated fatty acids, is particularly susceptible to the deleterious effects of oxidative stress; this can lead to loss of membrane integrity, protein damage, and neuronal dysfunction. Recent studies have shown that social phobia, depression, anxiety, and other neuropsychiatric disorders result in signs of oxidative stress such as increased reactive oxygen generation and decreased antioxidant capacity (Arranz et al., 2007;Bouayed et al., 2007). There is increasing evidence that oxidati...

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Section: Biochemical and Molecular Assaysmentioning

confidence: 99%

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Masood

Nadeem²,

Mustafa³

et al. 2008

J Pharmacol Exp Ther

Self Cite

199

168

View full text Add to dashboard Cite

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“…The airway responsiveness was assessed by whole body plethysmography using the chambers obtained from Buxco (Max II; Buxco Systems; Troy, NY) as described previously by our laboratory (40). This system enables the measurement of airway obstruction using a dimensionless parameter called enhanced pause (Penh).…”

Section: Real-time Pcr For Expression Of Icam-1 Vcam-1 and Il-5 Genesmentioning

confidence: 99%

Involvement of A₁adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

Ponnoth

Nadeem

Tilley

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Poor lung function and respiratory disorders like asthma have a positive correlation with the development of adverse cardiovascular events. Increased adenosine levels are associated with lung inflammation that could lead to altered vascular responses and systemic inflammation. We hypothesized that asthmatic lung inflammation has systemic effects through A 1 adenosine receptors (A1AR) and investigated the effects of aerosolized adenosine on vascular reactivity and inflammation, using A1AR knockout (A1KO) and corresponding wild-type (A1WT) mice that were divided into three experimental groups each: control (CON), allergen sensitized and challenged (SEN), and SEN ϩ aerosolized adenosine (SEN ϩ AD). Animals were sensitized with ragweed (200 g ip; days 1 and 6), followed by 1% ragweed aerosol challenges (days 11 to 13). On day 14, the SEN ϩ AD groups received one adenosine aerosol challenge (6 mg/ml) for 2 min, and aortae were collected on day 15. 5=-N-ethylcarboxamidoadenosine (NECA; nonselective adenosine analog) induced concentration-dependent aortic relaxation in the A 1WT CON group, which was impaired in the A1WT SEN and SEN ϩ AD groups. All groups of A 1KO mice showed similar (no significant difference) concentration-dependent relaxation to NECA. The A 1WT SEN and SEN ϩ AD groups had a significantly higher contraction to selective A 1 agonist 2-chloro-N 6 -cyclopentyladenosine (CCPA) compared with the CON group. Western blot data showed that aortic A 1AR expression was significantly increased in WT SEN and SEN ϩ AD mice compared with CON mice. Gene expression of ICAM-1 and IL-5 was significantly increased in allergic A 1WT aorta and were undetected in the A1KO groups. A1WT allergic mice had significantly higher airway hyperresponsiveness (enhanced pause) to NECA, with adenosine aerosol further enhancing it. In conclusion, allergic A 1WT mice showed altered vascular reactivity, increased airway hyperresponsiveness, and systemic inflammation. These data suggest that A 1AR is proinflammatory systemically in this model of allergic asthma.

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“…To set the relative unit to 1, ΔΔCT was calculated by subtraction of the ΔCT calibrator value (A 1 AR ΔCT values in A2AWT). The fold difference in gene expression of the target was calculated as the average value from 2 −ΔΔCT+s and 2 −ΔΔCT−s [17,23].…”

Section: Real-time Rt Pcr For Mouse Coronary Arteriesmentioning

confidence: 99%

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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Enhanced airway reactivity and inflammation in A_2Aadenosine receptor-deficient allergic mice

Cited by 55 publications

References 44 publications

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Involvement of A₁adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

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

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Enhanced airway reactivity and inflammation in A2Aadenosine receptor-deficient allergic mice

Cited by 55 publications

References 44 publications

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Involvement of A1adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma

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

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Enhanced airway reactivity and inflammation in A_2Aadenosine receptor-deficient allergic mice

Involvement of A₁adenosine receptors in altered vascular responses and inflammation in an allergic mouse model of asthma