Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination.

Objectives: Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs. Methods: Using the well-established murine model for immune-driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed. Results: Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4+ T-cell cytokine production as well as increased myelination in the spinal cords of co-treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits. Conclusion: This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine-fingolimod combination providing enhanced benefits.

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

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.

The Salvinorin Analogue, Ethoxymethyl Ether Salvinorin B, Promotes Remyelination in Preclinical Models of Multiple Sclerosis.

Multiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating therapies; however, prototypical KOR agonists, such as U50,488 have side effects, which limit clinical use. In the current study, we investigated a Salvinorin A analog, ethoxymethyl ether Salvinorin B (EOM SalB) in two preclinical models of demyelination in C57BL/6J mice. We showed that in cellular assays EOM SalB was G-protein biased, an effect often correlated with fewer KOR-mediated side effects. In the experimental autoimmune encephalomyelitis model, we found that EOM SalB (0.1-0.3 mg/kg) effectively decreased disease severity in a KOR-dependent manner and led to a greater number of animals in recovery compared to U50,488 treatment. Furthermore, EOM SalB treatment decreased immune cell infiltration and increased myelin levels in the central nervous system. In the cuprizone-induced demyelination model, we showed that EOM SalB (0.3 mg/kg) administration led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. Overall, EOM SalB was effective in two preclinical models of multiple sclerosis and demyelination, adding further evidence to show KOR agonists are a promising target for remyelinating therapies.