Inhibition of the neuroactive opioid growth factor (OGF) alters the blood levels of important pro- and anti-inflammatory proteins in mice with multiple sclerosis (MS)-like disease. The recognition of this regulatory response may represent a new way to monitor disease progression and treatment response in MS.
These findings were reported in a study published in the journal Experimental Biology and Medicine, titled “Modulation of the OGF–OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis.” The study was led by researchers at Penn State University.
Understanding the underlying mechanisms involved in MS and finding ways to tackle them is crucial for improving early diagnosis, monitoring disease progression, and patient care.
For many years, researchers at Penn State have been focused on understanding the benefits of low-dose naltrexone and its relation with OGF in health and disease, including MS.
Naltrexone is marketed with the brand name ReVia, among others. This drug is used routinely off-label to treat MS and other autoimmune diseases, as it has demonstrated to it can reduce fatigue, lessen pain, and confer a general feeling of well-being to patients.
Its mode of action is not fully understood, but it is known to block the interaction of the neuroactive OGF with its receptor OGFr. In addition, low-dose naltrexone and OGF were shown to prevent the proliferation of active immune cells in mice with MS-like disease.
To further evaluate the role of OGF and low-dose naltrexone in MS, researchers treated mice with naltrexone and analyzed its impact on blood levels of pro- and anti-inflammatory signaling proteins (cytokines).
Results showed that after 10 days, MS mice had increased levels in seven out of 10 tested cytokines. Treatment with OGF or low-dose naltrexone was found to specifically increase the levels of the pro-inflammatory IL-6 cytokine, and significantly reduce the levels of anti-inflammatory IL-10 protein.
Two other pro-inflammatory proteins, TNF-α and IFN-γ, also were found to be increased in MS mice compared to healthy animals. While TNF-α levels were unaltered upon OGF or low-dose naltrexone treatment, IFN-γ was reduced at 10 days, but still present at higher-than-normal levels after 20 days of therapy.
To validate its findings, the team analyzed the levels of the identified signaling proteins in blood samples collected from 14 MS patients and eight non-MS volunteers. Six MS patients were undergoing treatment with Copaxone (glatiramer acetate), and four of them had relapsing-remitting MS (RRMS). Four other RRMS patients and one primary progressive MS (PPMS) patient were receiving Copaxone plus low-dose naltrexone; three RRMS patients were receiving low-dose naltrexone alone.
The analysis revealed that IL-10 serum values were comparable between non-MS controls and all MS patients on low-dose naltrexone alone, or Copaxone alone. Patients treated with both Copaxone and naltrexone presented a broad range of IL-10 serum values “that were significantly different from MS subjects receiving LDN [low-dose naltrexone] only,” the researchers wrote.
In contrast, IL-6 cytokine was found to be significantly elevated in MS patients treated only with Copaxone compared to patients receiving low-dose naltrexone alone or together with Copaxone.
“These data suggest that IL-6, a pro-inflammatory marker is very responsive to OGF and LDN therapy, and thus may be involved in other mechanistic pathways associated with the OGF-OGFr axis,” the researchers wrote.
“Identification of inflammatory cytokines that have expression profiles mediated by OGF or LDN [low-dose naltrexone] therapy increase our panel of potential biomarkers for MS,” Patricia McLaughlin, PhD, said in a press release. McLaughlin is professor of neural and behavioral sciences at Penn State, and senior author of the study.
“We hope that continued research will identify more specific cytokines and allow us to assemble a reliable panel of minimally invasive biomarkers related to the etiology and progression of MS,” she added.
Additional long-term human and mouse studies are needed to further evaluate if IL-6 and IL-10 are “appropriate markers to monitor progression of MS,” the researchers emphasized. Still, the team believes this study demonstrates that at least IL-6, IL-10, TNF-α, and IFN-γ, together with OGF, can be useful biomarkers to monitor MS.
“McLaughlin and colleagues have researched OGF signaling for several decades, and this seminal discovery of dysregulation in OGF expression in MS patients, and animal models, is very exciting and could lead to prognostic biomarkers for this autoimmune disorder,” concluded Steven R. Goodman, PhD, editor-in-chief of the journal in which the study was published.