Dataset Information

Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease.

ABSTRACT:

Objectives

Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. There is currently no cure for MS, and finding effective treatments to prevent disease progression has been challenging. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists like U50,488 are not suitable for clinical use because of a poor side-effect profile, nalfurafine is a potent, clinically used KOR agonist with a favorable side-effect profile.

Methods

Using the experimental autoimmune encephalomyelitis (EAE) model, the effect of therapeutically administered nalfurafine or U50,488 on remyelination, CNS infiltration and peripheral immune responses were compared. Additionally, the cuprizone model was used to compare the effects on non-immune demyelination.

Results

Nalfurafine enabled recovery and remyelination during EAE. Additionally, it was more effective than U50,488 and promoted disease reduction when administered after chronic demyelination. Blocking KOR with the antagonist, nor-BNI, impaired full recovery by nalfurafine, indicating that nalfurafine mediates recovery from EAE in a KOR-dependent fashion. Furthermore, nalfurafine treatment reduced CNS infiltration (especially CD4⁺ and CD8⁺ T cells) and promoted a more immunoregulatory environment by decreasing Th17 responses. Finally, nalfurafine was able to promote remyelination in the cuprizone demyelination model, supporting the direct effect on remyelination in the absence of peripheral immune cell invasion.

Conclusions

Overall, our findings support the potential of nalfurafine to promote recovery and remyelination and highlight its promise for clinical use in MS.

SUBMITTER: Denny L

PROVIDER: S-EPMC7811802 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease.

Denny Lisa L Al Abadey Afnan A Robichon Katharina K Templeton Nikki N Prisinzano Thomas E TE Kivell Bronwyn M BM La Flamme Anne C AC

Clinical & translational immunology 20210117 1

<h4>Objectives</h4>Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to the myelin sheath, resulting in physical and cognitive disability. There is currently no cure for MS, and finding effective treatments to prevent disease progression has been challenging. Recent evidence suggests that activating kappa opioid receptors (KOR) has a beneficial effect on the progression of MS. Although many KOR agonists like U50,488 are not suitable for clinical use ...[more]

PMID: 33489124

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Project description:Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR)-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-?. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas with p75NTR/Sox2-positive cells. This study provides novel insights into the involvement of Schwann cells in CNS remyelination under natural occurring CNS inflammation. Targeting p75NTR/Sox2-expressing Schwann cells to enhance their differentiation into competent remyelinating cells appears to be a promising therapeutic approach for inflammatory/demyelinating CNS diseases.

Project description:Background and objective The impact of COVID-19 infection and the effect of COVID-19 vaccinations on patients with demyelinating central nervous system disease in low middle income countries (LMIC's) have not been reported in detail earlier. We sought to identify risk factors associated with COVID-19 infection and the role of vaccination in order to develop management guidelines relevant to our patients. Methods A total of 621 patients from our registry that included 297 MS and 324 non MS disorders (Aquaporin- 4 antibody positive [50], Myelin oligodendrocyte glycoprotein antibody positive [81], seronegative [162] and clinically isolated syndrome [31]) were contacted. COVID-19 infection and vaccination status were queried. Patients who self reported COVID-19 infection based on a positive RT PCR report were compared with non infected patients to identify factors associated with susceptibility for COVID-19 infection. Univariate and multivariate analysis of potential risk factors included demographic and clinical features, body mass index (BMI), presence of comorbidities, absolute lymphocyte count, treatment types and vaccination status. Results Sixty seven patients with MS and 27 with non MS disorders developed COVID-19 infection. Among them 81 patients had mild infection and remained quarantined at home. All 13 patients who needed hospitalization recovered. Vaccination status was known in 582 patients among whom 69.8% had completed or taken one dose of vaccine at the time of inquiry. Majority of treated patients (61.3%) were on nonspecific immunosuppressants. In univariate analysis, presence of ≥1 comorbidity was significantly associated with COVID-19 infection in both MS (p value 0.01, OR-2.28, 95%CI- 1.18- 4.4) and non MS patients (p- 0.001, OR-4.4, 95% CI-1.88-10.24). In the latter, BMI ≥ 30 (p-0.04, OR-3.27, 95% CI- 0.98- 10.87) and EDSS score ≥ 3 (p-0.02, OR- 2.59,95% CI- 1.08- 6.23) were other significant associations. History of prior COVID-19 vaccination was associated with reduced frequency of COVID- 19 infection among MS (p- 0.001,OR- 0.24,95% CI- 0.13- 0.43) and non MS patients (p- 0.0001,OR-0.14, 95% CI- 0.058- 0.35). In multivariate analysis presence of comorbidities significantly increased and prior vaccination significantly reduced frequency of COVID-19 infection for both MS and related disorders. Concurrent disease modifying treatments showed a trend for association with infection. In the unvaccinated group, patients on disease modifying treatment were significantly at risk of infection, 81.5% unvaccinated and treated versus 18.5% who were unvaccinated and untreated (p- 0.0001, OR-10.1, 95% CI-0.56-2.11). Conclusion Frequency and severity of COVID-19 infection was low among our patient cohort. Higher rate of infection in the treated group was significantly seen among unvaccinated patients. Our preliminary results suggests that in LMIC's, where “off label therapies” with inexpensive immunosuppressives are the main disease modifying drugs, mRNA vaccinations appear safe and effective against severe COVID-19 infection.

Dataset Information

Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease.

Objectives

Methods

Results

Conclusions

Publications

Nalfurafine reduces neuroinflammation and drives remyelination in models of CNS demyelinating disease.

Similar Datasets

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