scholarly journals Featured Article: Modulation of the OGF–OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis

2018 ◽  
Vol 243 (4) ◽  
pp. 361-369 ◽  
Author(s):  
Michael D Ludwig ◽  
Ian S Zagon ◽  
Patricia J McLaughlin
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokine ◽  
Low Dose ◽  
Serum Levels ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Low Dose Naltrexone ◽  
Experimental Autoimmune

The endogenous neuropeptide opioid growth factor, chemically termed [Met5]-enkephalin, has growth inhibitory and immunomodulatory properties. Opioid growth factor is distributed widely throughout most tissues, is autocrine and paracrine produced, and interacts at the nuclear-associated receptor, OGFr. Serum levels of opioid growth factor are decreased in patients with multiple sclerosis and in animals with experimental autoimmune encephalomyelitis suggesting that the OGF-OGFr pathway becomes dysregulated in this disease. This study begins to assess other cytokines that are altered following opioid growth factor or low-dose naltrexone modulation of the OGF-OGFr axis in mice with experimental autoimmune encephalomyelitis using serum samples collected in mice treated for 10 or 20 days and assayed by a multiplex cytokine assay for inflammatory markers. Cytokines of interest were validated in mice at six days following immunization for experimental autoimmune encephalomyelitis. In addition, selected cytokines were validated with serum from MS patients treated with low-dose naltrexone alone or low-dose naltrexone in combination with glatiramer acetate (Copaxone®). Experimental autoimmune encephalomyelitis mice had elevated levels of 7 of 10 cytokines. Treatment with opioid growth factor or low-dose naltrexone resulted in elevated expression levels of the IL-6 cytokine, and significantly reduced IL-10 values, relative to saline-treated experimental autoimmune encephalomyelitis mice. TNF-γ values were increased in experimental autoimmune encephalomyelitis mice relative to normal, but were not altered by opioid growth factor or low-dose naltrexone. IFN-γ levels were reduced in opioid growth factor- or low-dose naltrexone-treated experimental autoimmune encephalomyelitis mice relative to saline-treated mice at 10 days, and elevated relative to normal values at 20 days. Validation studies revealed that within six days of immunization, opioid growth factor or low-dose naltrexone modulated IL-6 and IL-10 cytokine expression. Validation in human serum revealed markedly reduced IL-6 cytokine levels in MS patients taking low-dose naltrexone relative to standard care. In summary, modulation of the OGF-OGFr pathway regulates some inflammatory cytokines, and together with opioid growth factor serum levels, may begin to form a panel of valid biomarkers to monitor progression of multiple sclerosis and response to therapy. Impact statement Modulation of the opioid growth factor (OGF)–OGF receptor (OGFr) alters inflammatory cytokine expression in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Multiplex cytokine assays demonstrated that mice with chronic EAE and treated with either OGF or low-dose naltrexone (LDN) had decreased expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and the anti-inflammatory cytokine IL-10 within 10 days or treatment, as well as increased serum expression of the pro-inflammatory cytokine IL-6, relative to immunized mice receiving saline. Multiplex data were validated using ELISA kits and serum from MS patients treated with LDN and revealed decreased in IL-6 levels in patients taking LDN relative to standard care alone. These data, along with serum levels of OGF, begin to formulate a selective biomarker profile for MS that is easily measured and effective at monitoring disease progression and response to therapy.

scholarly journals Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone

2017 ◽  
Vol 242 (15) ◽  
pp. 1524-1533 ◽  
Author(s):  
Michael D Ludwig ◽  
Ian S Zagon ◽  
Patricia J McLaughlin
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Low Dose ◽  
Endogenous Opioids ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Multiple Sclerosis Patients ◽  
Low Dose Naltrexone ◽  
Experimental Autoimmune

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone’s efficacy for fatigue, Crohn’s disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met5]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met5]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met5]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met5]-enkephalin or β-endorphin in normal mice. Thus, [Met5]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met5]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

scholarly journals Intermittent blockade of OGFr and treatment of autoimmune disorders

2018 ◽  
Vol 243 (17-18) ◽  
pp. 1323-1330 ◽  
Author(s):  
Ian S Zagon ◽  
Patricia J McLaughlin
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Disorders ◽  
Cell Replication ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Experimental Autoimmune

The opioid growth factor (OGF)–OGF receptor (OGFr) axis is present in normal and abnormal cells and tissues, and functions to maintain homeostatic cell replication. OGF is an inhibitory growth factor that upregulates p16 and/or p21 cyclin-dependent inhibitory kinases to slow cell replication. Blockade of this regulatory pathway can be intermittent or complete with the end result being depressed or accelerated, respectively, cell proliferation and growth. Intermittent blockade of the OGF–OGFr pathway with lose doses of naltrexone (LDN), a general opioid receptor antagonist, has been studied clinically in a number of autoimmune diseases, including fibromyalgia, Crohn’s, and multiple sclerosis (MS). Serum enkephalin levels were decreased in patients with MS relative to subjects with other neurological disorders. The intermittent blockade of OGFr by LDN results in a biofeedback mechanism that upregulates serum enkephalin levels. Clinical studies have reported that LDN is beneficial in enhancing quality of life, reducing fatigue, and increasing motor activity in humans with fibromyalgia, Crohn’s, or MS. LDN treatment is well tolerated even after several years of therapy. Preclinical investigations using experimental autoimmune encephalomyelitis (EAE), an animal model of MS mediated by T and B lymphocyte activation, demonstrate that immunization alone resulted in reduced enkephalin (i.e. OGF) levels. Therapy with LDN restored serum enkephalin levels in EAE mice resulting in improved EAE behavioral scores and diminished CNS pathology. This mini-review summarizes both preclinical and clinical data and focuses on the role of serum enkephalins resulting from intermittent blockade of OGFr by LDN in autoimmune disorders. Impact statement This mini-review presents information on the intermittent blockade of the opioid growth factor (OGF)–OGF receptor (OGFr) axis by low-dose naltrexone (LDN), and the role of enkephalin (i.e. OGF) in autoimmune disorders, specifically multiple sclerosis, Crohn’s, and fibromyalgia. Clinical reports on subjects taking LDN have documented reduced fatigue, few side-effects, and improved overall health. Preclinical studies on mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, revealed that immunization for EAE reduces serum OGF. Intermittent OGFr blockade with LDN restores serum enkephalin levels that correlate with reduced behavioral and pathological signs of EAE; LDN also increases enkephalin levels in naïve mice. The interplay between LDN, and the onset and treatment of autoimmune diseases, chronic pain, and other addictive behaviors requires further investigation, but highlights a central role for enkephalins and intermittent blockade of the OGF–OGFr pathway in pathogenesis and treatment of these disorders.

Opioid growth factor suppresses expression of experimental autoimmune encephalomyelitis

2010 ◽  
Vol 1310 ◽  
pp. 154-161 ◽  
Author(s):  
Ian S. Zagon ◽  
Kristen A. Rahn ◽  
Robert H. Bonneau ◽  
Anthony P. Turel ◽  
Patricia J. McLaughlin
Keyword(s):  
Growth Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Opioid Growth Factor ◽  
Experimental Autoimmune
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