Ghrelin Alleviates Gastric Inflammation in Ovariectomized Rats

Abstract

Background: There is a link between aging and gastric diseases. The aim of this study was to evaluate the effects of ghrelin on gastric morphology in ovariectomized rats.
Materials and Methods: Under ketamine-chlorpromazine anesthesia (100 mg/kg, 0.75 mg/kg), Sprague-Dawley rats (n=12) underwent bilateral ovariectomy, while control group (G1) had sham-surgery (n=6). Four weeks after surgery, half of ovariectomized rats (G3) were treated intraperitoneally with ghrelin (1 mg/kg/week) for 4 weeks, while others (G2) were not treated. Rats were euthanized by cardiac puncture at the end of 8th weeks, and serum levels of estradiol were measured. Gastric tissue was analyzed with light and scanning electron microscopy.
Results: Increased body weights in ovariectomized (G2 and G3) rats (p<0.001) recorded at the end of 2 months was not changed with ghrelin. In ovariectomized groups (G2 and G3) serum estradiol levels were reduced (p<0.05) verifying altered gonadal hormone status. Apical mucus cells and gastric pits were observed in regular morphology in sham group while vascular dilatation and degeneration was observed in ovariectomized rats (G2 and G3), whereas in the ghrelin group (G3) it was generally observed similar to sham group (G1).
Conclusion: In conclusion, mild dyslipidemia and hepatic degeneration in early post-menopausal period appear to be attenuated by ghrelin treatment, and it is required further investigations.
Key words: Ghrelin, Inflammation, Postmenopause, Gastric mucosa

Ghrelin Overektomi Yapılmış Sıçanlarda Gastrik İnflamasyonu Düzeltir

Abstract

AMAÇ: İlerleyen yaş ve mide hastalıkları arasında bir ilişki vardır. Bu çalışmanın amacı, ghrelinin overektomize (OVT) sıçanlarda mide morfolojisi üzerindeki etkilerini değerlendirmektir. GEREÇ VE YÖNTEMLER: Ketamin-klorpromazin anestezisi altında (100 mg / kg, 0,75 mg / kg), Sprague-Dawley sıçanlarına (n = 12) çift taraflı OVT, kontrol grubunda taklit cerrahi uygulandı (n = 6). Ameliyattan dört hafta sonra, OVT sıçanlarının yarısı 4 hafta boyunca intraperitoneal olarak ghrelin (1 mg / kg / hafta) ile tedavi edildi, kontrol grubuna serum fizyolojik uygunlandı. 8. hafta sonunda kardiyak ponksiyon ile ötenazi yapılarak östrojen düzeyi ölçüldü. Mide dokusunda ışık ve taramalı elektron mikroskopu ile histolojik inceleme yapılmıştır. BULGULAR: 2 ay sonunda OVT ile artan (p<0,001) vücut ağırlıkları, ghrelin ile değişmedi. Serum östradiol düzeyi değişmiş gonadal hormon durumu doğrulayacak şekilde azaldı (p<0,05). Taklit cerrahi grubunda düzenli morfolojide apikal mukus hücreleri ve gastrik pitler gözlendi. OVT grubunda vaskülar dilatasyon ve dejenerasyonla karakterize hasar gözlenirken ghrelin grubunda genel olarak düzenli morfolojide izlendi. SONUÇ: Sonuç olarak menopoz sonrası erken dönemde hafif gastrik hasarın ghrelin tedavisi ile azaldığı ve bu alanda daha fazla araştırmaya ihtiyaç duyulduğu görülmektedir.

Keywords

• ghrelin
• inflamasyon
• postmenopoz
• gastrik mukoza

References

1. Marcucci G, Brandi ML. Rare causes of osteoporosis. Clin Cases Miner Bone Metab. 2015;12(2):151-6.
2. LaFleur J, Rillamas-Sun E, Colón-Emeric CS, Knippenberg KA, Ensrud KE, Gray SL, et al. Fracture Rates and Bone Density Among Postmenopausal Veteran and Non-Veteran Women From the Women’s Health Initiative. The Gerontologist 2016 Feb;56 Suppl 1(Suppl 1):S78-90.
3. Valle J, Kekki M, Sipponen P, Ihamäki T, Siurala M. Long-term course and consequences of Helicobacter pylori gastritis. Results of a 32-year follow-up study. Scand J Gastroenterol 1996; 31:546–50.
4. Gazizova RR, Novikova AV, Vinogradova MA. Age-related features of inflammatory and immune responses of the gastric mucosa in women with chronic gastritis. Patol Fiziol Eksp Ter. 1995; 4:32-4.
5. Fotouk-Kiai M, Hoseini SR, Meftah N, Ghadimi R, Bijani A, Noreddini H et al. Relationship between Helicobacter pylori infection (HP) and bone mineral density (BMD) in elderly people.Caspian J Intern Med. 2015; 6(2):62-6.
6. Heidari B. Helicobacter pylori infection and osteoporosis in elderly patients. Caspian J Intern Med. 2015; 6(2):48-50.
7. Kim HW, Kim YH, Han K, Nam GE, Kim GS, Han BD, et al. Atrophic gastritis: a related factor for osteoporosis in elderly women. PLoS One. 2014; 9(7):e101852 . Kakehasi AM, Rodrigues CB, Carvalho AV, Barbosa AJA. Chronic gastritis and bone mineral density in women. Dig Dis Sci 2009,54(4):819-24.
8. Eastell R, Vieira NE, Yergey AL, Wahner HW, Silverstein MN, Kumar R, et al. Pernicious anaemia as a risk factor for osteoporosis. Clin Sci (Lond) 1992;82(6):681-5.

9. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999 Dec 9;402(6762):656-60.
10. Dass NB, Munonyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, et al. Growth hormone secretagogue receptors in rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience. 2003;120(2):443-53
11. Aydin S, Ozercan IH, Dagli F, Aydin S, Dogru O, Celebi S, et al. Ghrelin immunohistochemistry of gastric adenocarcinoma and mucoepidermoid carcinoma of salivary gland. Biotech Histochem. 2005;80(3-4):163-8.
12. D. DeBoer, M. The Use of Ghrelin and Ghrelin Receptor Agonists as a Treatment for Animal Models of Disease: Efficacy and Mechanism. Current Pharmaceutical Design. 2012;18(31), 4779–99.
13. Granada M, Priego T, Martin AI, Villanua MA, Lopez-Caldoran A. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats. Am J Physiol Endocrinol Metab 2005; 288: E486–E492.
14. Yukawa M, Weigle DS, Davis CD, Marck BT, Wolden-Hanson T. Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery. Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1453-60
15. Lippl F, Erdmann J, Steiger A, Lichter N, Czogalla-Peter C, Bidlingmaier M, et al. Low-dose ghrelin infusion--evidence against a hormonal role in food intake. Regul Pept. 2012; 174(1-3):26-31. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194-8.
16. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000; 407:908–13.
17. Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB. Diet-induced obesity causes ghrelin resistance in arcuate npy/agrp neurons. Endocrinology 2010; 151: 4745-55.
18. Álvarez-Castro P, Pena L, Cordido F. Ghrelin in obesity, physiological and pharmacological considerations. Mini Rev Med Chem. 2013;13(4):541-52.
19. Rosická M, Krsek M, Matoulek M, Jarkovská Z, Marek J, Justová V, et al. Serum ghrelin levels in obese patients: the relationship to serum leptin levels and soluble leptin receptors levels. Physiol Res. 2003;52(1):61-6.
20. Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2014;100(2):508-15.
21. Gallagher J, Riggs BL, Deluca HF. Effect of Estrogen on Calcium Absorption and Serum Vitamin D Metabolites in Postmenopausal Osteoporosis, The Journal of Clinical Endocrinology & Metabolism. 1980; 51(6):1359-64.
22. Nordin BEC, Need AG, Morris HA, O'Loughlin PD, Horowitz M. Effect of age on calcium absorption in postmenopausal women Am J Clin Nutr 2004; 80(4): 998-1002.
23. Heaney RP, Recker RR, Stegman MR and Moy A J. Calcium absorption in women: Relationships to Calcium intake, Estrogen status, and age. J Bone Miner Res 1989; 4: 469–75.
24. Sipponen P, Härkönen M. Hypochlorhydric stomach: a risk condition for calcium malabsorption and osteoporosis? Scand J Gastroenterol 2009; 45(2):133-8.
25. Zhao D, Zhan Y, Zeng H, Moyer MP, Mantzoros CS, Pothoulakis C. Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated NF-kappaB pathway in human colonic epithelial cells. J Cell Biochem. 2006 Apr 15;97(6):1317-27.
26. Maduzia D, Matuszyk A, Ceranowicz D, Warzecha Z, Ceranowicz P, Fyderek K, et al. The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats. J Physiol Pharmacol. 2015;66(6):875-85.
27. De Smet B, Thijs T, Moechars D, Colsoul B, Polders L, Ver Donck L, et al. Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice. Neurogastroenterol Motil. 2009; 21(1):59-70.
28. Şen LS, Karakoyun B, Yeğen C, Akkiprik M, Yüksel M, Ercan F, et al. Treatment with either obestatin or ghrelin attenuates mesenteric ischemia-reperfusion-induced oxidative injury of the ileum and the remote organ lung. Peptides. 2015; 71:8-19.
29. Cieszkowski J, Warzecha Z, Ceranowicz P. 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. J Physiol Pharmacol. 2017;68(4):609-17.
30. Kalkan Ç, Soykan I. The Relations Among Serum Ghrelin, Motilin and Gastric Emptying and Autonomic Function in Autoimmune Gastritis. Am J Med Sci. 2018;355(5):428-33.
31. Sirchak ES, Patskun SV. Interrelation between ghrelin and gastrin in patients with combination of chronic gastritis and type 2 diabetes mellitus. Wiad Lek. 2018;71(2 pt 1):311-14.
32. Ichikawa H, Sugimoto M, Sakao Y, Sahara S, Ohashi N, Kato A, et al. Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients. World J Gastroenterol. 2016; 22(47):10440-49.