Protective Effects of Melatonin Against the Damages of Neuroendocrine-immune Induced by Lipopolysaccharide in Diabetic Rats

Abstract

The present study was to determine the protective effects of melatonin (MLT) against the damages of neuroendocrine-immune induced by lipopolysaccharide (LPS) in streptozotocin (STZ)-induced diabetic rats, and to analyze the parameters related to diabetes and oxidative stress. A total of 70 male Sprague-Dawley rats were assigned to this experiment. 10 of rats received STZ intraperitoneally (i.p.) alone as diabetic control; 40 of rats as the Diabetes+LPS received STZ plus LPS i.p. after induction of diabetes with STZ, then assigned to sub-groups as MLT_0.1 mg, MLT_1 mg, and Vehicle group, received two doses MLT and vehicle, i.p., respectively, q6 h for 12 h after LPS administration; and the remaining served as normal and LPS control. LPS significantly increased the serum levels of TNF-α and IL-6 in normal and diabetic rats; LPS also dramatically increased the plasma concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone. Both 0.1 and 1 mg/kg MLT doses significantly decreased the serum levels of TNF-α and IL-6. Significant inhibitory effects of MLT (1 mg/kg) were observed on the plasma concentrations of CRH, ACTH, and corticosterone of the HPA axis. The beneficial effects of MLT, such as the antioxidant activity and maintaining glucose homoeostasis, were also observed in this study, this resulted in a protective effect against the damages caused by LPS in STZ-induced diabetic rats. This finding probably provides a new approach for preventing the undesirable effects of the vicious cycle of hyperglycemia and stress factors such as severe infection in diabetic patients.

melatonin - lipopolysaccharide - diabetes - cytokines - HPA axis

References

• 1 Araya AV, Pavez V, Perez C. et al . Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE₂secretion in whole blood from Type 1 diabetes mellitus patients with or without aggressive periodontitis.  Eur Cytokine Netw. 2003;  14 128-133
• 2 Borjigin J, Li XD, Snyder SH. et al . The pineal gland and melatonin:molecular and pharmacologic regulation.  Ann Rev Pharmacol Toxicol. 1999;  39 53-65
• 3 Bellipanni G, Bianchi P, Pierpaoli W. et al . Effects of melatonin in per-menopausal and menopausal women: a randomized and placebo controlled study.  Exp Gerontol. 2001;  36 297-310
• 4 Chan O, Inouye K, Vranic M. et al . Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin-diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity.  Endocrinology. 2002;  143 1761-1768
• 5 Chan O, Inouye K, Riddell MC. et al . Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis.  Minerva Endocrinolpgica. 2003;  28 87-102
• 6 Cam M, Yavuz O, Guven A. et al . Protective effects of chronic melatonin treatment against renal injury in streptozotocin-induced diabetic rats.  J Pineal Res. 2003;  35 212-220
• 7 Defrance R, Quera-Salva MA. Therapeutic applications of melatonin and related compounds.  Hormone Research. 1998;  49 142-146
• 8 Derlacz RA, Sliwinska M, Piekutowska A. et al . Melatonin is more effective than taurine and 5-hydroxytryptophan against hyperglycemia-induced kidney-cortex tubules injury.  J Pineal Res. 2007;  42 203-209
• 9 Turek FW. Circadian rhythms.  Horm Res. 1998;  49 109-113
• 10 Geoffriau M, Brun J, Chazot G. et al . The physiology and pharmacology of melatonin in humans.  Hormone Research. 1998;  49 136-141
• 11 Gohil BC, Rosenblum LA, Coplan JD. et al . Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity.  CNS Spectrums. 2001;  6 581-589
• 12 Gorgun FM, Kokoglu E, Gumustas MK. et al . Effects of melatonin on plasma S-nitrosoglutathione and glutathione in streptozotocin-treated rats.  Journal of Toxicology and Environmental Health. Part A. 2004;  67 979-986
• 13 Konakchieva R, Mitev Y, Almeiga OF. et al . Chronic melatonin treatment and the hypothalamus-pituitary axis in the rat: attenuation of the secretary response to stress and effects on hypothalamic neuropeptide content and release.  Biology Cell. 1997;  89 587-596
• 14 Konakchieva R, Mitev Y, Almeiga OF. et al . Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat.  Neuroendocrinology. 1998;  67 171-180
• 15 Kostoglou-Athanassiou I, Treachert DF, Wheeler MJ. et al . Melatonin administration and pituitary hormone secretion.  Clinical Endocrinology. 1998;  48 31-37
• 16 Kurcer Z, Parlakpinar H, Vardi N. et al . Protective effects of chronic melatonin treatment against renal ischemia/reperfusion injury in streptozotocin-induced diabetic rats.  Exp Clin Endocrinol Diabetes. 2007;  115 365-371
• 17 Kanter M, Uysal H, Karaca T. et al . Depression of glucose levels and partial restoration of pancreatic beta-cell damage by melatonin in streptozotocin-induced diabetic rats.  Arch Toxicol. 2006;  80 362-369
• 18 Luboshitzky R. Endocrine activity during sleep.  J Pediatr Endocrinol Metab. 2000;  13 13-20
• 19 Oktem F, Ozguner F, Yilmaz HR. et al . Melatonin reduces urinary excretion of N-acetyl-beta-D-glucosaminidase, albumin and renal oxidative markers in diabetic rats.  Clin and Exp Pharmacol & Physiol. 2006;  33 95-101
• 20 Pickup JC, Chusney GD, Thomas SM. et al . Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes.  Life Sciences. 2000;  67 291-300
• 21 Ran RQ, Lu AG, Zhang L. et al . Hsp70 promotes TNF-mediated apoptosis by binding IKK γ and impairing NF-kB survival signaling.  Gene Develop. 2004;  18 1466-1481
• 22 Sacco S, Aquilini L, Ghezzi P. et al . Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro.  Eur J Pharmacol. 1998;  343 249-255
• 23 Soop M, Duxbury H, Agwunobi AO. et al . Euglycemic hyperinsulinemia augments the cytokine and endocrine responses to endotoxin in humans.  Am J Physiol Endocrinol Metab. 2002;  282 E1276-1285
• 24 Sudnikovich EJ, Maksimchik YZ, Zabrodskaya SV. et al . Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats.  Eur J Pharmacol. 2007;  569 180-187
• 25 Wehr TA. Effect of seasonal changes in daylength on human neuroendocrine function.  Horm Res. 1998;  49 118-124
• 26 Winiarska K, Fraczyk T, Malinska D. et al . Melatonin attenuates diabetes-induced oxidative stress in rabbits.  J Pin Res. 2006;  40 168-176
• 27 Yavuz O, Cam M, Bukan N. et al . Protective effect of melatonin on beta-cell damage in streptozotocin-induced diabetes in rats.  Acta Histochemistry. 2003;  105 261-266
• 28 Zhong LY, Jin H, Gao F. et al . Exogenous melatonin inhibited the function of pituitary-adrenal in alloxan-induced diabetic rats.  Chin J of Endocrinol Metab. 2003;  19 141-143

Correspondence