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.
Digital Object Identifier (DOI)
This study was funded by the Ministry of Business, Innovation, and Employment (RTVU1503 to ACL, BK and TP), The Neurological Foundation of New Zealand (#1639PG to BK, ACL and TP), The Health Research Council of New Zealand (#18/063 to BK, ACL, and TP), The Great New Zealand Trek (to ACL), the Kate Parsonson Scholarship (to LD), the Wellington Medical Research Foundation (2018/294 to LD & ACL), and the National Institute on Drug Abuse (DA018151 to TEP).
Denny, Lisa; Al Abadey, Afnan; Robichon, Katharina; Templeton, Nikki; Prisinzano, Thomas E.; Kivell, Bronwyn M.; and La Flamme, Anne C., "Nalfurafine Reduces Neuroinflammation and Drives Remyelination in Models of CNS Demyelinating Disease" (2021). Pharmaceutical Sciences Faculty Publications. 156.
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