Intranasal administration of NECA can induce both anti-inflammatory and pro-inflammatory effects in BALB/c mice: evidence for A 2A receptor sub-type mediation of NECA-induced anti-inflammatory effects.
The role of adenosine in allergic inflammation is unclear. This study investigated the effects of the non-selective adenosine receptor agonist, 5-N-ethylcarboxamidoadenosine (NECA), on immunized only and immunized and airway challenged mice. The adenosine receptor sub-type(s) mediating the NECA effects and the A(2A) receptor mRNA expression were also investigated. In mice that were only immunized, intranasal NECA (1 mM) administration caused a significant increase in bronchoalveolar lavage total cell count (TCC), neutrophils and eosinophils (>1.5-, >6 and >60-fold, respectively). Two and four intranasal ovalbumin (OVA) challenges induced a significant (P < 0.05) increase in TCC (>2.1- and >4-fold, respectively) and eosinophils (>350- and >1700-fold, respectively). Real-time PCR analysis showed that the A(2A) receptor sub-type mRNA was significantly increased (P < 0.05) in the lung tissue of immunized mice following both two and four OVA challenges. NECA (0.3 mM) treatment caused a significant reduction in the increase induced by the two and four OVA challenges in the TCC by 46.1% and 56.6%, respectively, eosinophils by 70.1% and 75.6%, respectively, and in the A(2A) receptor sub-type mRNA by 43.2% and 41.0%, respectively. Treatment with the A(2A) receptor antagonist, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), SCH-58261, completely reversed both the NECA-mediated reduction in TCC and eosinophilia. Moreover, OVA challenge of immunized mice, over 2 consecutive days, resulted in a significant (P < 0.05) increase in TCC (4.5-fold) and eosinophils (>2000-fold) that was detected 72 h later. NECA (0.3 mM) treatment, at 24 and 48 h post OVA challenge, significantly reduced the increase in both TCC and eosinophils by 45.0% and 74.8%, respectively. Our data show that in immunized, but not OVA-challenged mice, high dose of NECA (1 mM) induces an inflammatory airway response. In contrast, in models of inflammation, NECA, at mainly 0.3 mM, induces a significant anti-inflammatory effect when administered prior to the induction of airway inflammation or therapeutically following its establishment. The data also indicate that the anti-inflammatory action of NECA seems to be mediated via the A(2A) receptor sub-type and hence the use of selective A(2A) receptor agonists as potential therapeutic agents in the treatment of inflammatory diseases such as asthma should be investigated further.
El-Hashim
Ahmed Z
AZ
Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. ahmed.elhashim@hsc.edu.kw
Abduo
Heba T
HT
Rachid
Ousama M
OM
Luqmani
Yunus A
YA
Al Ayadhy
Bushra Y
BY
Alkhaledi
Ghanim M
GM
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000008:administration & dosage* / Q000627:therapeutic use*; D000281:Administration, Intranasal; D000818:Animals; D000893:Anti-Inflammatory Agents; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D007114:Immunization; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000235:genetics; D012137:Respiratory System / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use*
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000893:Anti-Inflammatory Agents; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); D010047:Ovalbumin