Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

McLaughlin

2017

Exp Biol Med (Maywood)

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. [Met 5 ]-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 MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. b-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. AbstractLow-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 [Met 5 ]-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 [Met 5 ]-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, [Met 5 ]-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 [Met 5 ]-enkephalin or b-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor)...

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

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

Ludwig

McLaughlin

2017

Exp Biol Med (Maywood)

“…Given the importance that OGF therapy was effective for relapsing EAE when the drug was given at the time of disease induction (30), a study was conducted on the effects of OGF treatment (31) or LDN (32) on established RR-EAE, with injections beginning 2 days after initial clinical signs of disease. Mice were immunized with subcutaneous injections of 100 mg of myelin proteolipid protein [139][140][141][142][143][144][145][146][147][148][149][150][151] .…”

Section: Rr-eae With Ogf or Ldn Treatment Beginning At The Time Of Esmentioning

confidence: 99%

“…In the first model, C57Bl6/J black mice were immunized with myelin oligodendrocytic glycoprotein (MOG ), whereas the SJL/J white mouse along with proteolipid protein (PLP ) is required to establish the RR-EAE (25)(26)(27)(28)(29)(30)(31)(32). Each animal model was established and subgroups treated with either OGF or LDN beginning either at the time of immunization (induction of disease) or after disease symptoms were visible for 2 days (established disease).…”

Section: Preclinical Studies Of Enkephalins and Eaementioning

confidence: 99%

“…Two different animal models were established to study progressive EAE (25)(26)(27)(28)(29) and relapsing-remitting EAE (RR-EAE) (30)(31)(32). In the first model, C57Bl6/J black mice were immunized with myelin oligodendrocytic glycoprotein (MOG ), whereas the SJL/J white mouse along with proteolipid protein (PLP ) is required to establish the RR-EAE (25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Preclinical Studies Of Enkephalins and Eaementioning

confidence: 99%

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Endogenous Opioids in the Etiology and Treatment of Multiple Sclerosis

Multiple Sclerosis: Perspectives in Treatment and Pathogenesis

McLaughlin

2017

Self Cite

Endogenous opioids are enkephalins and endorphins that are primarily produced in the brain and have multiple actions throughout the body. Enkephalins and endorphins act at opioid receptors and their activity can be blocked by opioid antagonists. A small pentapeptide termed opioid growth factor (OGF), and chemically termed [Met 5 ]-enkephalin, has been shown to have causative and therapeutic roles in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Enkephalin levels are reduced in animals and humans during MS relapses, and may play a role in etiology. Exogenous therapy with OGF or endogenous stimulation of OGF by low dosages of naltrexone (LDN) reverse the course of progressive EAE and limit the number of relapses in relapsingremitting EAE. Individuals prescribed LDN report less fatigue and a better quality of life while using LDN. This chapter summarizes the information from studies using two different animal models of EAE, as well as two different treatment regimens of two different compounds-OGF or LDN. In all investigations, the presence of enkephalins resulted in beneficial effects.

Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis

Patel

J of Neuroscience Research

Pearce-Clawson

et al. 2021

Self Cite

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that primarily affects women during the second or third decade of life. The mechanism is hypothesized to involve unregulated peripheral inflammation resulting in bloodbrain barrier damage, and eventual axonal damage and demyelination. Based on this understanding, the animal model of MS, experimental autoimmune encephalomyelitis (EAE), often is utilized to study lymphocyte activation. Therapeutic paradigms of exogenous opioid growth factor (OGF) or low-dose naltrexone (LDN) treatment can modulate EAE, but little is reported regarding OGF or LDN effects on peripheral inflammation, microglia activation, and/or macrophage proliferation. Moreover, little is known about differential responses to LDN or OGF relative to the duration and timing of treatment. Utilizing a female mouse model of EAE, two treatment regimens were established to investigate differences between prophylactic treatment and traditional therapy initiated at the time of disease presentation. Prophylactic OGF or LDN treatment delayed the onset of behavior, suppressed neutrophil replication, and curtailed lymphocyte proliferation which ultimately improved behavioral outcome. Traditional therapy with OGF or LDN reversed behavioral deficits, restored OGF and IL-17 serum levels, and inhibited microglial activation within 8 days. Reduced serum OGF levels in untreated EAE mice correlated with increased microglia activation within lumbar spinal cords. Both treatment regimens of OGF or LDN reduced activated microglia, whereas only prophylactic treatment prevented CNS macrophage aggregation. These data demonstrate that the timing of LDN or OGF treatment initiation alters outcomes and can prevent or reverse behavioral deficits, cytokine activation, and spinal cord pathology.