2-Furoyl-LIGRL-NH_2, a potent agonist for proteinase-activated receptor-2, as a gastric mucosal cytoprotective agent in mice

摘要

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 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-NH_2 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-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 μmol 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 0.1-0.5 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 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.