Increase of β-Endorphin Secretion by Syringin, an Active Principle of Eleutherococcus senticosus, to Produce Antihyperglycemic Action in Type 1-like Diabetic Rats

Abstract

We employed streptozotocin-induced diabetic rats (STZ-diabetic rats) as type 1 diabetes-like animal models to investigate the mechanism(s) of antihyperglycemic action produced by syringin, an active principle purified from the rhizome and root parts of Eleutherococcus senticosus (Araliaceae). Bolus intravenous (i. v.) injection of syringin dose-dependently decreased the plasma glucose of STZ-diabetic rats in 30 minutes in a way parallel to the increase of plasma β-endorphin-like immunoreactivity (BER). Syringin enhanced BER release from the isolated adrenal medulla of STZ-diabetic rats in a concentration-dependent manner from 0.001 to 10 μmol/l. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of syringin (1 mg/kg, i. v.) including the plasma glucose-lowering effect and the plasma BER-elevating effect. Also, syringin failed to lower plasma glucose in the presence of μ-opioid receptor antagonists and/or in the μ-opioid receptor knockout diabetic mice. In conclusion, the obtained results suggest that syringin can enhance the secretion of β-endorphin from adrenal medulla to stimulate peripheral μ-opioid receptors resulting in a decrease of plasma glucose in diabetic rats lacking insulin.

streptozotocin-induced diabetic rats - syringin - β-endorphin - μ-opioid receptors

References

• 1 Jeffcoate SL. Diabetes control and complications: the role of glycated haemoglobin, 25 years on.  Diabet Med. 2004;  21 657-665
• 2 Lindstrom J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, Uusitupa M, Tuomilehto J. Finnish Diabetes Prevention Study Group . The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity.  Diabetes Care. 2003;  26 3230-3236
• 3 Davydov M, Krikorian AD. Eleutherococcus senticosus (Rupr. & Maxim. Maxim. (Araliaceae) as an adaptogen: a closer look.  J Ethnopharmacol. 2000;  72 345-393
• 4 Kwan CY, Zhang WB, Sim SM, Deyama T, Nishibe S. Vascular effects of Siberian ginseng (Eleutherococcus senticosus): endothelium-dependent NO- and EDHF-mediated relaxation depending on vessel size.  Naunyn Schmiedebergs Arch Pharmacol. 2004;  369 473-480
• 5 Asano K, Takahashi T, Miyashita M, Matsuzaka A, Muramatsu S, Kuboyama M, Kugo H, Imai J. Effect of Eleutheroccocus senticosus extract on human physical working capacity.  Planta Med. 1986;  3 175-177
• 6 Goulet ED, Dionne IJ. Assessment of the effects of Eleutherococcus senticosus on endurance performance.  Int J Sport Nutr Exerc Metab. 2005;  15 75-83
• 7 Hikino H, Takahashi M, Otake K, Konn C. Isolation and hypoglycemic activity of eleutherans A, B, C, D, E, F, and G: glycans of Eleutherococcus senticosus roots.  J Nat Prod. 1986;  49 293-297
• 8 Cho JY, Nam KH, Kim AR, Park J, Yoo ES, Baik KU, Yu YH, Park MH. In-vitro and in-vivo immunomodulatory effects of syringin.  J Pharm Pharmacol. 2001;  53 1287-1294
• 9 Ruijun Z, Jinkang Q, Gnanghua Y, Baozhen W, Xiulan W. Medicinal protection with Chinese herb-compound against radiation damage.  Aviat Space Environ Med. 1990;  61 729-731
• 10 Choi J, Shin KM, Park HJ, Jung HJ, Kim HJ, Lee YS, Rew JH, Lee KT. Anti-inflammatory and antinociceptive effects of sinapyl alcohol and its glucoside syringin.  Planta Med. 2004;  70 1027-1032
• 11 Curry DL, Li CH. Stimulation of insulin secretion by beta-endorphin (1-27 and 1-31).  Life Sci. 1987;  40 2053-2058
• 12 Cheng JT, Liu IM, Tzeng TF, Tsai CC, Lai TY. Plasma glucose lowering effect of β-endorphin in streptozotocin-induced diabetic rats.  Horm Metab Res. 2002;  34 570-576
• 13 Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN. μ-Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality.  Brain Res Mol Brain Res. 1998;  54 321-326
• 14 Liu IM, Chi TC, Shiao GC, Lin MT, Cheng JT. Loss of plasma glucose lowering response to cold stress in opioid μ-receptor knock-out diabetic mice.  Neurosci Lett. 2001;  307 81-84
• 15 Niu HS, Hsu FL, Liu IM, Cheng JT. Syringin as the active principle of Eleutherococcus senticosus to lower plasma glucose in streptozotocin-induced diabetic rats.  Planta Med. , (submitted)
• 16 Hwang SL, Liu IM, Tzeng TF, Cheng JT. Activation of imidazoline receptors in adrenal gland to lower plasma glucose in streptozotocin-induced diabetic rats.  Diabetologia. 2005;  48 767-775
• 17 Wohaieb SA, Godin DV. Alterations in free radical tissue-defense mechanisms in streptozotocin-induced diabetes in rat. Effect of insulin treatment.  Diabetes. 1987;  36 1014-1018
• 18 Vargo T, Rossier J, Minick S, Ling N, Rivier C, Vale W, Bloom F. β-endorphin and adrenal corticotropin are secreted concomitantly by the pituitary gland.  Science. 1977;  197 1367-1369
• 19 Hanbauer I, Kelly GD, Saiani L, Yang HY. [Met5]-enkephalin-like peptides of the adrenal medulla: release by nerve stimulation and functional implications.  Peptides. 1982;  3 469-473
• 20 Arefolov VA, Dmitriev AD, Tennov AV, Val'dman AV. Detection of the pro-opiomelanocortin peptide fragments-beta-endorphin and ACTH-in the adrenals of rats and mice by immunohistochemistry.  Biull Eksp Biol Med. 1986;  101 445-447
• 21 Hsu CT, Liu IM, Cheng JT. Increase of beta-endorphin biosynthesis in the adrenal gland of streptozotocin-induced diabetic rats.  Neurosci Lett. 2002;  318 57-60
• 22 Liu IM, Chen WC, Cheng JT. Mediation of beta-endorphin by isoferulic acid to lower plasma glucose in streptozotocin-induced diabetic rats.  J Pharmacol Exp Ther. 2003;  307 1196-1204
• 23 Gourlay GK. Advances in opioid pharmacology.  Support Care Cancer. 2005;  13 153-159
• 24 Cheng JT, Liu IM, Chi TC, Tzeng TF. Increase of opioid μ-receptor gene expression in streptozotocin-induced diabetic rats.  Horm Metab Res. 2001;  33 467-471

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