Opioid growth factor suppresses expression of experimental autoimmune encephalomyelitis.
ABSTRACT Naltrexone, an opioid antagonist, has been shown to modulate expression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, suggesting that endogenous opioids are inhibitory trophic factors in EAE. In the present study, we investigated the effects of one native opioid peptide, opioid growth factor ([Met(5)]-enkephalin), on the onset and progression of EAE. C57Bl/6 mice injected with myelin oligodendrocyte glycoprotein (MOG) received daily injections of 10 mg/kg OGF (MOG+OGF) or saline (MOG+Vehicle). Over 60% of the MOG+OGF animals did not exhibit behavioral signs of disease (EAE) in contrast to 100% of the mice in the MOG+Vehicle group. The severity and disease indices of EAE in the OGF-treated mice were markedly reduced from MOG+Vehicle cohorts. By day 30, 60% of MOG+OGF mice had a remission, relative to 4% in the MOG+Vehicle group. MOG-injected mice receiving OGF had significant reductions in activated astrocytes and damaged neurons compared to MOG+Vehicle animals. Unlike MOG+Vehicle and MOG+OGF mice with behavioral signs of disease, MOG+OGF animals without manifestation of disease had no lumbar spinal cord demyelination. Both OGF and OGF receptor were detected in splenic-derived T lymphocytes by immunohistochemistry. OGF treatment decreased both DNA synthesis and cell proliferation in comparison to vehicle-treated T cell lymphocyte cultures. These results indicate that an endogenous opioid, OGF, inhibits the onset and progression of EAE, and suggest that clinical studies on the use of OGF treatment for MS are merited.
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is induced by immunization of mice with myelin oligodendrocytic glycoprotein (MOG35-55) injections, and after 9 days, mice develop behavioral signs of chronic progressive EAE. Proliferation of T and B cells located in peripheral lymph tissues such as spleen and inguinal lymph nodes of C57BL/6J mice are stimulated. The opioid growth factor-opioid growth factor receptor (OGF-OGFr) axis has been shown to effectively limit progression of chronic EAE when mice are treated at the time of induction or at time of established disease. In addition to repressed behavioral profiles, spinal cord neuropathology is diminished in mice treated with OGF or low dosages of naltrexone (LDN). However, there is little or no information on peripheral lymphocyte dynamics following immunization of mice with MOG antigen and treatment with OGF or LDN. Six-week old female mice were immunized with MOG35-55 and were injected intraperitoneally with OGF or a low dosage of naltrexone (LDN) beginning at the time of immunization; saline-injected immunized mice served as controls. Normal mice received saline for all injections. Periodically over a 2 week period, spleens and inguinal lymph nodes were removed, total lymphocytes counted, and subpopulations of CD4+ and CD8+ specific T-cells, as well as B lymphocytes, were determined by flow cytometry. On day 15 of treatment, lumbar spinal cord tissue was removed; CNS lymphocytes isolated, and assayed for Th1, Th2, and Th17 markers by flow cytometry. Exogenous OGF or endogenous OGF following LDN suppressed T and B lymphocyte proliferation in the spleen and inguinal lymph nodes of MOG-immunized mice. Suppression of peripheral immune cell CD4+ and CD8+ T cell proliferation at 5 and 12 days correlated with reductions in clinical behavior. EAE mice treated with OGF for 15 days displayed elevated Th1 and Th17 cells; no subpopulations of Th2-specific T cells were noted. OGF or LDN repress proliferation of CD4+ and CD8+T cells and B220+ B lymphocytes in the spleen and lymph nodes of immunized mice within a week of immunization. These data provide novel mechanistic pathways underlying the efficacy of OGF and LDN therapy for MS.BMC Immunology 04/2015; 16(1):24. DOI:10.1186/s12865-015-0093-0 · 2.25 Impact Factor
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ABSTRACT: Endogenious opiod met-enkephalin throughout previous research manifested cytoprotective and anti-inflammatory effects. Previous research suggests that met-enkephalin has cytogenetic effects. Reducement in the frequency of structural chromosome aberrations as well as a suppressive effect on lymphocyte cell cycle is found. It also reduces apoptosis in the blood samples of the patients with immune-mediated diseases. Met-enkephalin exerts immunomodulatory properties and induces stabilization of the clinical condition in patients with multiple Sclerosis (MS). The goal of the present research was to evaluate met-enkephalin in vitro effects on the number and type of chromosome aberrations in the peripheral blood lymphocytes of patients with MS. Our research detected disappearance of ring chromosomes and chromosome fragmentations in the cultures of the peripheral blood lymphocytes treated with met-enkephalin (1.2 μg/mL). However, this research did not detect any significant effects of met-enkephalin on the reduction of structural chromosome aberrations and disappearance of dicentric chromosomes. Chromosomes with the greatest percent of inclusion in chromosome aberrations were noted as: chromosome 1, chromosome 2 and chromosome 9. Additionally, we confirmed chromosome 14 as the most frequently included in translocations. Furthermore, met-enkephalin effects on the increase of the numerical aberrations in both concentrations applied were detected. Those findings should be interpreted cautiously and more research in this field should be conducted.
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ABSTRACT: Relapse-remitting multiple sclerosis is a chronic disease of the CNS that affects 350,000 individuals in the U.S, reducing the quality of life and often resulting in paralysis. Most current therapies do not target the underlying pathophysiology of multiple sclerosis (MS). This study examined the therapeutic efficacy of an endogenous peptide (opioid growth factor, OGF) known to inhibit cell replication in a receptor-mediated manner, utilizing a mouse model of relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). RR-EAE was induced by immunization of SJL/J mice with proteolipid protein. Two days following establishment of clinical disease, treatment with OGF (10mg/kg) or saline was initiated and mice were observed on a daily basis. OGF treated mice had markedly reduced clinical signs of disease over the course of 40 days. OGF treatment increased the incidence and lengthened the time of remissions relative to saline-treated mice with RR-EAE. OGF therapy also reduced relapses, and facilitated extended periods of mild disease. Neuropathological examination of lumbar spinal cord after 40 days of treatment revealed decreased numbers of Iba-1 and CD3+ reactive cells, suggesting that OGF inhibited proliferation of microglia/macrophages and T lymphocytes, as well as decreasing the number of proliferating activated astrocytes (Ki67 and GFAP dual labeled sections). Peptide treatment for 40 days diminished levels of demyelination in comparison to saline-treated mice with RR-EAE. These data are the first to demonstrate that exposure to OGF initiated at the time of established disease can reverse the course of RR-EAE and reduce neuropathological deficits. Copyright © 2015. Published by Elsevier Inc.Brain Research Bulletin 01/2015; 112. DOI:10.1016/j.brainresbull.2015.01.009 · 2.97 Impact Factor