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

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 blood–brain 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.

This is the peer reviewed version of the following article: [Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis. Journal of Neuroscience Research 100, 2 p551-563 (2021)], which has been published in final form at https://doi.org/10.1002/jnr.24983. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions: https://authorservices.wiley.com/author-resources/Journal-Authors/licensing/self-archiving.html#3.

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Work Title Timing of treatment with an endogenous opioid alters immune response and spinal cord pathology in female mice with experimental autoimmune encephalomyelitis
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Open Access
Creators
  1. Chirag Patel
  2. Ian S. Zagon
  3. Mason Pearce-Clawson
  4. Patricia J. McLaughlin
Keyword
  1. Experimental autoimmune encephalomyelitis
  2. [Met5]-enkephalin
  3. Low Dose Naltrexone
  4. Inflammatory cytokines
  5. Microglia
  6. Macrophages
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Journal of Neuroscience Research
Publication Date February 1, 2022
Publisher Identifier (DOI)
  1. https://doi.org/10.1002/jnr.24983
Deposited February 24, 2023

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Version 1
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  • Created
  • Added Manuscript.Timing_of_Treatment.docx
  • Added Creator Chirag Patel
  • Added Creator Ian S. Zagon
  • Added Creator Mason Pearce-Clawson
  • Added Creator Patricia J. McLaughlin
  • Published
  • Updated Keyword Show Changes
    Keyword
    • Experimental autoimmune encephalomyelitis, [Met5]-enkephalin, Low Dose Naltrexone, Inflammatory cytokines, Microglia, Macrophages
  • Updated