Leptin, a product of ob gene controlling food intake, has recently been detected in the stomach and shown to be released by CCK and implicated in gastroprotection against various noxious agents but it is unknown whether centrally applied
leptin influences
ischemia-reperfusion (I/R)-induced gastric erosions that progress into deeper gastric ulcerations. In this study we compared the effects of
leptin and
CCK-8 applied intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) on gastric mucosal lesions induced by I/R and topical application of 75%
ethanol. Several major series of Wistar rats were used to examine the effects of
leptin and CCK applied centrally on gastroprotection against I/R and
ethanol in rats with A)
vagotomy by cutting of vagal nerves, B) suppression of
NO-synthase with L-NNA (20 mg/kg i.p.), C) inactivation of sensory nerves by
capsaicin (125 mg/kg s.c.) and D) inhibition of
CGRP receptors with CGR(8-37) (100 microg/kg i.p.) applied with or without the i.c.v. pretreatment with
leptin or CCK-8. Rats were anesthetized 1 h after
ethanol administration or at 3 h and 3 days upon the end of
ischemia to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma
leptin and
gastrin levels by radioimmunoassay (RIA).
Leptin (0.1-20 microg/kg i.p.) dose-dependently attenuated gastric lesions induced by 75%
ethanol and I/R; the dose reducing these lesions by 50% (ED50) was 8 microg/kg and 6 microg/kg, respectively and this protective effect was similar to that obtained with CCK-8 applied in a standard dose of 10 microg/kg i.p. This protective effect of
leptin was accompanied by a significant increase in GBF and plasma
gastrin levels whereas CCK-8 increased plasma
leptin levels but failed to affect plasma
gastrin levels.
Leptin and CCK-8 applied i.c.v. in a dose of 625 ng/rat reduced significantly the area of I/R induced gastric lesions and raised the GBF and plasma
leptin levels with the extent similar to those achieved with peripheral administration of
leptin or CCK-8 (10 microg/kg i.p.). The protective and hyperemic effects of centrally administered
leptin or CCK-8 (625 ng/rat i.c.v.) were completely abolished by
vagotomy and significantly attenuated by sensory
denervation with
capsaicin or by CGRP antagonist,
CGRP(8-37). The pretreatment with L-NNA to inhibit
NO-synthase activity attenuated significantly the protective and hyperemic effects of CCK but not those of
leptin while
capsaicin denervation counteracted
leptin-induced protection and rise in the GBF but attenuated significantly those of CCK. We conclude that: 1) central
leptin exerts a potent gastroprotective activity against I/R-induced gastric erosions that progress into deeper gastric lesions and this protection depends upon vagal activity and sensory nerves and involves
hyperemia probably mediated by NO and 2)
leptin mimics the gastroprotective effect of CCK and may be implicated in the protective and hyperemic actions of this
peptide against mucosal damage evoked by I/R.