Therapeutic effect of exogenous ghrelin in the healing of gingival ulcers is mediated by the release of endogenous growth hormone and insulin-like growth factor-1.

Ghrelin, an acylated 28-amino acid polypeptide, was primary isolated from the stomach, and the stomach is a main source of circulating ghrelin. Ghrelin strongly and dose-dependently stimulates release of growth hormone from the anterior pituitary, as well as increases food intake and fat deposition. Previous studies showed that ghrelin exhibits protective and therapeutic effect in different parts of the gastrointestinal system, including the oral cavity. The aim of present study was to examine the role of growth hormone and insulin-like growth factor-1 (IGF-1) in the healing of gingival ulcers. Studies were performed on rats with the intact pituitary gland and hypophysectomized rats. In anesthetized rats, chronic ulcers of the gum were induced by acetic acid. Rats were treated intraperitoneally twice a day with saline or ghrelin (4, 8 or 16 nmol/kg/dose) for six days. In pituitary-intact rats, administration of ghrelin significantly increased serum concentration of growth hormone and IGF-1 and this effect was associated with a significant increase in the healing rate of gingival ulcers. Moreover, treatment with ghrelin increased mucosal blood flow and DNA synthesis in the gum, while a local inflammation was decreased what was observed as a reduction in mucosal concentration of pro-inflammatory interleukin-1ß. Hypophysectomy decreased serum level of growth hormone below a detection limit; whereas serum concentration of IGF-1 was reduced by 90%. On the other hand, removal of the pituitary gland was without any significant effect on the healing rate of gingival ulcers or on the ulcer-induced increase in DNA synthesis and concentration of pro-inflammatory interleukin-1ß in gingival mucosa. Administration of ghrelin failed to affect serum level of growth hormone and IGF-1 in hypophysectomized rats, and was without any effect on the healing rate of gingival ulcers, mucosal blood flow, DNA synthesis or concentration of interleukin-1ß in gingival mucosa. Neither induction of gingival ulcers nor hypophysectomy nor administration of ghrelin significantly affected serum concentration of pro-inflammatory interleukin-1ß. We concluded that endogenous growth hormone and IGF-1 were involved in the therapeutic effect of exogenous ghrelin in the healing of gingival mucosa damage.

The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats.

Ghrelin has been primarily shown to exhibit protective and therapeutic effect in the gut. Pretreatment with ghrelin inhibits the development of acute pancreatitis and accelerates pancreatic recovery in the course of this disease. In the stomach, ghrelin reduces gastric mucosal damage induced by ethanol, stress or alendronate, as well as accelerates the healing of acetic acid-induced gastric and duodenal ulcer. The aim of present studies was to investigate the effect of pretreatment with ghrelin on the development of acetic acid-induced colitis. Studies have been performed on male Wistar rats. Animals were treated intraperitoneally with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose). Saline or ghrelin was given twice: 8 and 1 h before induction of colitis. Colitis was induced by a rectal enema with 1 ml of 4% solution of acetic acid and the severity of colitis was assessed 1 or 24 hours after induction of inflammation. Rectal administration of acetic acid induced colitis in all animals. Damage of colonic wall was seen at the macroscopic and microscopic level. This effect was accompanied by a reduction in colonic blood flow and mucosal DNA synthesis. Moreover, induction of colitis significantly increased mucosal concentration of pro-inflammatory interleukin-1ß (IL-1ß), activity of myeloperoxidase and concentration of malondialdehyde (MDA). Mucosal activity of superoxide dismutase (SOD) was reduced. Pretreatment with ghrelin reduced the area and grade of mucosal damage. This effect was accompanied by an improvement of blood flow, DNA synthesis and SOD activity in colonic mucosa. Moreover, ghrelin administration reduced mucosal concentration of IL-1ß and MDA, as well as decreased mucosal activity of myeloperoxidase. Administration of ghrelin protects the large bowel against the development of the acetic acid-induced colitis and this effect seems to be related to the ghrelin-evoked anti-inflammatory and anti-oxidative effects.

Role of hormonal axis, growth hormone - IGF-1, in the therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis.

Ghrelin is a ligand for growth hormone secretagogue receptor and stimulates release of growth hormone (GH). Recent studies have shown that treatment with ghrelin exhibits protective and therapeutic effect in the course of experimental pancreatitis. The aim of present study was to examine the role of GH and insulin-like growth factor-1 (IGF-1) in these effects. Acute pancreatitis was induced by cerulein. Study was performed on pituitary-intact hypophysectomized rats. Ghrelin was administered twice a day at the dose of 8 nmol/kg/dose. IGF-1 was given twice a day at the dose of 20 nmol/kg/dose. The severity of acute pancreatitis was assessed 0 h or 1, 2, 3, 5 and 10 days after the last dose of cerulein. Administration of cerulein led to the development of acute edematous pancreatitis. In pituitary-intact rats, treatment with ghrelin reduced biochemical indexes of the severity of acute pancreatitis and morphological signs of pancreatic damage, leading to faster regeneration of the pancreas reduction in serum concentration of pro-inflammatory interleukin-1ß and decrease in serum activity of amylase and lipase. These effects were accompanied with an improvement of pancreatic blood flow and an increase in pancreatic DNA synthesis. Hypophysectomy delayed the healing of the pancreas and abolished the therapeutic effect of ghrelin. In hypophysectomized rats with pancreatitis, treatment with IGF-1 exhibits therapeutic effect similar to that observed in ghrelin-treated rats with the intact pituitary. We conclude that therapeutic effect of ghrelin in cerulein-induced pancreatitis is indirect and depends on the release of GH and IGF-1.

Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats.

UNLABELLED: Recent studies have shown that ghrelin exhibits gastroprotective effects. The aim of present study was to examine the influence of ghrelin administration on the healing of chronic gastric and duodenal ulcers and to evaluate the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this process. In pituitary-intact or hypophysectomized rats, chronic gastric and duodenal ulcers were induced by acetic acid. After induction of ulcers, rats were treated intraperitoneally twice a day with saline, ghrelin (4, 8 or 16 nmol/kg/dose) or IGF-1 (20 nmol/kg/dose) for six or ten days. In animals with intact pituitary, treatment with ghrelin increased serum level of GH and IGF-1. These effects were accompanied by the increase in mucosal cell proliferation, mucosal blood flow and healing rate of gastric and duodenal ulcers. After hypophysectomy, the significant increase in serum level of endogenous ghrelin was observed, but the healing of gastric and duodenal ulcers was delayed. This effect was accompanied by a significant decrease in serum concentration of endogenous GH and IGF-1, and reduction in mucosal blood flow and DNA synthesis. In hypophysectomized rats, administration of exogenous ghrelin was without any effect on serum level of GH and IGF-1, healing rate of gastroduodenal ulcers or mucosal cell proliferation. In contrast to this effect, administration of IGF-1 increased mucosal cell proliferation, healing rate of gastroduodenal ulcers and mucosal blood flow in hypophysectomized rats. CONCLUSION: Treatment with ghrelin accelerates healing of chronic gastroduodenal ulcers and this effect is mediated by the release of endogenous GH and IGF-1.