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 (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-NH2, 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-NH2, administered intraperitoneally (i.p.) at 0.3 - 1 mumol 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 mumol 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 mumol 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 mumol kg(-1) caused prompt salivation in anesthetized mice, whereas its oral administration at 0.003 - 1 mumol 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-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.