2‐Furoyl‐LIGRL‐NH 2 , a potent agonist for proteinase‐activated receptor‐2, as a gastric mucosal cytoprotective agent in mice

1 Proteinase‐activated receptor‐2 (PAR 2 ), expressed in capsaicin‐sensitive sensory neurons, plays a protective role in gastric mucosa. The present study evaluated gastric mucosal cytoprotective effect of 2‐furoyl‐LIGRL‐NH 2 , a novel highly potent PAR 2 agonist, in ddY mice and in wild‐type and PAR 2 ‐knockout mice of C57BL/6 background. 2 Gastric mucosal injury was created by oral administration of HCl/ethanol solution in the mice. The native PAR 2 ‐activating peptide SLIGRL‐NH 2 , administered intraperitoneally (i.p.) at 0.3–1  μ mol kg −1 in combination with amastatin, an aminopeptidase inhibitor, but not alone, revealed gastric mucosal protection in ddY mice, which was abolished by ablation of capsaicin‐sensitive sensory neurons. 3 I.p. administration of 2‐furoyl‐LIGRL‐NH 2 at 0.1  μ mol kg −1 , without combined treatment with amastatin, exhibited gastric mucosal cytoprotective activity in ddY mice, the potency being much greater than SLIGRL‐NH 2 in combination with amastatin. This effect was also inhibited by capsaicin pretreatment. 4 Oral administration of 2‐furoyl‐LIGRL‐NH 2 at 0.003–0.03  μ mol kg −1 also protected against gastric mucosal lesion in a capsaicin‐reversible manner in ddY mice. 5 I.p. 2‐furoyl‐LIGRL‐NH 2 at 0.1–0.3  μ mol kg −1 caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003–1  μ mol kg −1 was incapable of eliciting salivation. 6 In wild‐type, but not PAR 2 ‐knockout, mice of C57BL/6 background, i.p. administration of 2‐furoyl‐LIGRL‐NH 2 caused gastric mucosal protection. 7 Thus, 2‐furoyl‐LIGRL‐NH 2 is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR 2 in gastric mucosal protection and the selective nature of 2‐furoyl‐LIGRL‐NH 2 .British Journal of Pharmacology (2005) 144 , 212–219. doi: 10.1038/sj.bjp.0706059