Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2A adenosine receptor in rats.
OBJECTIVE
To determine whether a specific adenosine A(2A) receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines.


METHODS
Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 mug/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion.


RESULTS
Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8+/-7.75 mm and was reduced to 3.8+/-1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P<0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e.


CONCLUSIONS
The specific adenosine A(2A) receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.
Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita City 010-8543, Japan. odashima@doc.med.akita-u.ac.jp
Masaru
M
Odashima
Michiro
M
Otaka
Mario
M
Jin
Koga
K
Komatsu
Isao
I
Wada
Youhei
Y
Horikawa
Tamotsu
T
Matsuhashi
Natsumi
N
Hatakeyama
Jinko
J
Oyake
Reina
R
Ohba
Sumio
S
Watanabe
Joel
J
Linden
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001241:Aspirin / Q000633:toxicity*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D015232:Dinoprostone / Q000032:analysis; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000032:analysis; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C431129:ATL 146e; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003509:Cyclohexanecarboxylic Acids; D007375:Interleukin-1; D011687:Purines; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D015232:Dinoprostone; D001241:Aspirin