2‐Furoyl‐LIGRL‐NH2, a potent agonist for proteinase‐activated receptor‐2, as a gastric mucosal cytoprotective agent in mice

1 Proteinase‐activated receptor‐2 (PAR2), 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‐NH2, a novel highly potent PAR2 agonist, in ddY mice and in wild‐type and PAR2‐knockout mice of C57BL/6 background. 2 Gastric mucosal injury was created by oral administration of HCl/ethanol solution in the mice. The native PAR2‐activating peptide SLIGRL‐NH2, administered intraperitoneally (i.p.) at 0.3–1 μmol 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‐NH2 at 0.1 μmol kg−1, without combined treatment with amastatin, exhibited gastric mucosal cytoprotective activity in ddY mice, the potency being much greater than SLIGRL‐NH2 in combination with amastatin. This effect was also inhibited by capsaicin pretreatment. 4 Oral administration of 2‐furoyl‐LIGRL‐NH2 at 0.003–0.03 μmol kg−1 also protected against gastric mucosal lesion in a capsaicin‐reversible manner in ddY mice. 5 I.p. 2‐furoyl‐LIGRL‐NH2 at 0.1–0.3 μmol kg−1 caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003–1 μmol kg−1 was incapable of eliciting salivation. 6 In wild‐type, but not PAR2‐knockout, mice of C57BL/6 background, i.p. administration of 2‐furoyl‐LIGRL‐NH2 caused gastric mucosal protection. 7 Thus, 2‐furoyl‐LIGRL‐NH2 is considered a potent and orally available gastric mucosal protective agent. Our data also substantiate a role for PAR2 in gastric mucosal protection and the selective nature of 2‐furoyl‐LIGRL‐NH2. British Journal of Pharmacology (2005) 144, 212–219. doi:10.1038/sj.bjp.0706059