Hormonal
peptides like
ghrelin,
orexin A (OXA) or nesfatin-1 not only regulate appetite, which is their basic biological function, but also contribute to mechanisms responsible for maintaining integrity of the gastric mucosa. Previous studies including those from our laboratory have revealed that their gastroprotective effect results from cooperation with other factors responsible for protection of the gastric mucosa, including
prostaglandin (PG) synthesis pathway,
nitric oxide (NO) and the sensory afferent fibres releasing the vasoactive
neurotransmitters. The aim of the present study was to determine whether
ghrelin,
orexin-A (OX-A) or nesfatin-1 with their protective effect on the gastric mucosa, also can modify the healing of chronic
gastric ulcers. Furthermore, an attempt was made to explain participation of these
peptides in healing processes of chronic
gastric ulcers with comorbid conditions for the human beings resulted from
diabetes mellitus. In our study, a model of
gastric ulcers caused by concentrated
acetic acid to induce the chronic
gastric ulcers was used, while the clinical condition corresponding to diabetes was induced by single injection of
streptozotocin (STZ). We found that
ghrelin, OX-A and nesfatin-1 accelerate dynamics of the
acetic acid ulcers healing, confirmed by a reduction in the
ulcer area and this effect was accompanied by an increase in gastric blood flow at the
ulcer margin. Destruction of sensory afferent fibres with
capsaicin or blocking of
vanilloid receptors with
capsazepine resulted in a significant reduction of
ghrelin, OX-A and nesfatin-1-induced acceleration of
ulcer healing. Similar results were obtained when an
NO-synthase blocker, L-NNA was used in a combination with these
peptides. Moreover, it was found that OX-A and nesfatin-1 failed to accelerate the healing process under diabetic condition because both these
hormones induced reduction in the
ulcer area and the increase in blood flow in normal, non-diabetic rats were completely lost in the group of animals with diabetes. Treatment with OX-A and nesfatin-1 increased
superoxide dismutase (SOD)
mRNA expression even in
acetic acid ulcers concurrent with diabetes. However, the treatment with OX-A and nesfatin-1 failed to alter the increase in gastric mucosal
mRNA expression for
ghrelin and
hypoxia-inducible factor 1-alpha (HIF-1α), this latter effect that had been strongly pronounced in diabetic animals. We conclude that the hormonal
peptides involved in the regulation of satiety and hunger such as
ghrelin, OX-A and nesfatin-1 contribute to the process of chronic
gastric ulcers healing cooperating with NO and sensory afferent nerve endings releasing vasoactive
neuropeptide CGRP. Furthermore, OX-A and nesfatin-1, the two relatively unrecognized
peptides, play an essential role in healing process of chronic
gastric ulcers activating the gastric blood flow at
ulcer margin and the mucosal regeneration and both
ulcer healing and accompanying
hyperemia at
ulcer margin are greatly impaired during diabetes. Possibly, loss of the healing effect of these
peptides during diabetes results from an interaction with radical generation processes as reflected by an increase of
mRNA expression for SOD as well as the failure of their attenuating activity on proinflammatory factors such as HIF-1α.