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Title: Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

Abstract

Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonistmore » may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.« less

Authors:
;  [1];  [2];  [3];  [4]
  1. Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)
  2. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)
  3. Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)
  4. Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of), E-mail: ghazikha@sina.tums.ac.ir
Publication Date:
OSTI Identifier:
21144127
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 232; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2008.06.020; PII: S0041-008X(08)00285-8; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLOOD; GLUCOSE; HYPERGLYCEMIA; INFLAMMATION; INSULIN; INTERFERON; MICE; PANCREAS; RECEPTORS; SECRETION; STREPTOZOCIN

Citation Formats

Amirshahrokhi, K., Dehpour, A.R., Hadjati, J., Sotoudeh, M., and Ghazi-Khansari, M. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice. United States: N. p., 2008. Web. doi:10.1016/j.taap.2008.06.020.
Amirshahrokhi, K., Dehpour, A.R., Hadjati, J., Sotoudeh, M., & Ghazi-Khansari, M. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice. United States. doi:10.1016/j.taap.2008.06.020.
Amirshahrokhi, K., Dehpour, A.R., Hadjati, J., Sotoudeh, M., and Ghazi-Khansari, M. 2008. "Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice". United States. doi:10.1016/j.taap.2008.06.020.
@article{osti_21144127,
title = {Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice},
author = {Amirshahrokhi, K. and Dehpour, A.R. and Hadjati, J. and Sotoudeh, M. and Ghazi-Khansari, M.},
abstractNote = {Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of {beta} cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a {mu}-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1{beta}, tumor necrosis factor-{alpha} and interferon-{gamma}] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of {beta} cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of {beta} cells and insulitis in the MLDS model of type 1 diabetes.},
doi = {10.1016/j.taap.2008.06.020},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 232,
place = {United States},
year = 2008,
month =
}
  • Highlights: ► We monitored long-term beta cell regeneration in neonatal mice treated with low dose STZ. ► Low-dose STZ neonatal female mice recovered blood glucose in 150 days. ► Glucose intolerance of the STZ treated mice significantly improved in 150 days. -- Abstract: Administration of streptozotocin (STZ) induces destruction of β-cells and is widely used as an experimental animal model of type I diabetes. In neonatal rat, after low-doses of STZ-mediated destruction of β-cells, β-cells regeneration occurs and reversal of hyperglycemia was observed. However, in neonatal mice, β-cell regeneration seems to occur much slowly compared to that observed in themore » rat. Here, we described the time dependent quantitative changes in β-cell mass during a spontaneous slow recovery of diabetes induced in a low-dose STZ mice model. We then investigated the underlying mechanisms and analyzed the cell source for the recovery of β-cells. We showed here that postnatal day 7 (P7) female mice treated with 50 mg/kg STZ underwent the destruction of a large proportion of β-cells and developed hyperglycemia. The blood glucose increased gradually and reached a peak level at 500 mg/dl on day 35–50. This was followed by a spontaneous regeneration of β-cells. A reversal of non-fasting blood glucose to the control value was observed within 150 days. However, the mice still showed impaired glucose tolerance on day 150 and day 220, although a significant improvement was observed on day 150. Quantification of the β-cell mass revealed that the β-cell mass increased significantly between day 100 and day 150. On day 150 and day 220, the β-cell mass was approximately 23% and 48.5% of the control, respectively. Of the insulin-positive cells, 10% turned out to be PCNA-positive proliferating cells. Our results demonstrated that, β-cell duplication is one of the cell sources for β-cell regeneration.« less
  • The objective of this study was to determine whether mature thymic-derived T-lymphocytes were required for streptozotocin (SZ)-induced insulitis. C57BL/KsJ male mice were immunocrippled by thymectomy at 3 wk of age followed 1 wk later by lethal irradiation (1000 R) and hematopoietic reconstitution with syngeneic bone marrow (pretreated with anti-Thy 1.2 antiserum and complement to eliminate mature T-lymphocytes). As a control for the systemic effects of lethal irradiation itself, thymus-intact males were also irradiated and reconstituted with anti-Thy-1.2-treated marrow cells. This latter treatment resulted in a reconstitution of functional T-lymphocytes. Independent of the presence or absence of functional T-lymphocytes, irradiation extensivelymore » damaged the testes and produced at least a 50% reduction in plasma testosterone levels. Focal leukocytic infiltrates of the exocrine pancreas were induced by the irradiation. Streptozotocin-induced insulitis was also observed regardless of the presence or absence of phytohemagglutinin-responsive T-lymphocytes. Both groups exhibited intact B-lymphocyte function as measured by proliferative responsiveness to lipopolysaccharide. We conclude that functional (mature) T-lymphocytes are not required to mediate the beta cytotoxicity of multiple low doses of SZ in inbred strains in which insulitis accompanies islet destruction. The ability of hydrocortisone to protect beta-cells from the direct cytotoxic action of SZ as well as to eliminate leukocytic infiltration in the pancreas would support the hypothesis that insulitis is a consequence of beta-cell destruction, in this model, rather than its cause.« less
  • Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiationmore » of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet. • Genistein modulation of neutrophils is associated with blood glucose levels.« less
  • In genetically susceptible strains of mice, repeated injections of a subdiabetogenic dose of streptozotocin induces the development of progressive insulin-dependent hyperglycemia. We showed previously that host T-cell functions play an obligatory etiologic role in this experimental disease by demonstrating that the athymic nude mouse is resistant to diabetes induction unless its T-cell functions are reconstituted by thymus graft. Here we show that lethal irradiation of euthymic (+/nu) mice of BALB/cBOM background causes selective resistance of the mice to the diabetogenic effects of the multiple low doses of streptozotocin without affecting their sensitivity to a high pharmacologic dose of the toxin.more » We also show that reconstitution of the irradiated mice with splenic lymphocytes causes the restoration of diabetes susceptibility. Lethally irradiated mice thus represent a useful experimental model for analyzing the host functions involved in the development of this disease. These results provide an additional support for the hypothesis that the induction of diabetes in this model system is mediated by an autoimmune amplification mechanism.« less
  • Peripheral nerve from experimentally diabetic rats exhibits lowered levels of myo-inositol (MI) and decreased incorporation of ({sup 3}H)MI into phosphatidylinositol (PI). There are indications that diminished PI turnover may be causally related to reduced Na{sup +}, K{sup +} -ATPase activity in diabetic nerve. The authors have investigated whether a metabolic compartment of MI that is essential for PI synthesis is decreased in this tissue. Sciatic nerve segments form streptozotocin-induced diabetic and age-matched normal rats were incubated in vitro with either {sup 32}P{sub i} or ({sup 3}H)cytidine in the presence of propranolol. This cationic amphiphilic agent redirected nerve phospholipid metabolism tomore » produce enhanced {sup 32}P incorporation into PI and decreased labeling of phosphatidylcholine and phosphatidyl-ethanolamine. The incorporation of ({sup 3}H)cytidine into CMP-PA in normal nerve increased up to 15-fold when 0.6 mM propranolol was present. These results strongly suggest the presence in nerve of a pool of MI that is not in equilibrium with the bulk of nerve MI and that is preferentially used for PI synthesis. This metabolic compartment is depleted in diabetic nerve but can be readily replenished by exogenous MI and may correspond to the MI pool that has been proposed to be required for the turnover of a portion of tissue PI involved in maintenance of normal Na{sup +}, K{sup +} -ATPase activity.« less