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.

Multiple Sclerosis and the Endogenous Opioid System

“…This study provides support that KOR ligands are directly acting on KORs expressed on OPCs and suggests that future studies should consider targeting this receptor for remyelination therapy (Mei et al, 2016). In line with these results, treatment with a selective KOR agonist, U50,488H, has been shown to enhance remyelination in lysolecithin-, hypoxia-, and cuprizone-induced demyelination models (Mei et al, 2016;Wang et al, 2018b), and has since been replicated in the EAE model using a delayed treatment schedule (Denny et al, 2021). Furthermore, Du et al (2016) found that administration of U50,488H reduced the severity of motor impairments in EAE mice through promoting oligodendrocyte differentiation and remyelination.…”

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

“…Similarly, Tangherlini et al ( 6 ) showed that prophylactic administration of quinoxaline-based KOR agonists reduced EAE severity in a KOR-dependent fashion. Denny et al ( 22 ) showed that therapeutic KOR agonist administration, where treatment starts after the initial onset of symptoms, led to a decrease in EAE disease scores, using both U50,488 (1.6 mg/kg) and nalfurafine (0.0003–0.1 mg/kg). This therapeutic administration tests the ability of KOR agonists to induce recovery rather the prophylactic treatment regimen that tests a combination of disease induction, progression and recovery.…”

“…Myelin was detected using luxol fast blue stain (LFB; Sigma-Aldrich). The protocol previously generated for Black gold II staining was modified ( 22 ) and is shown in Supplementary Figure 1 . Infiltrating immune cells in the spinal cord were detected using hematoxylin and eosin (H&E) stain and is shown in Supplementary Figure 2 .…”

“…The KOR is a G-protein coupled receptor, therefore, downstream signaling can occur via both the G-protein and β-arrestin pathways, with many of the negative side-effects, such as sedation and aversion, associated with the β-arrestin signaling pathways ( 20 ). The extremely G-protein biased KOR agonist, nalfurafine ( 21 ), significantly reduced EAE disease scores, increased remyelination and was more potent than U50,488 ( 22 ). Together these effects indicate that G-protein biased KOR agonists are highly effective at reducing EAE disease with reduced side effects and hold potential for the development of novel therapeutics to treat MS.…”

Cuprizone feed formulation influences the extent of demyelinating disease pathology

“…For Black-Gold II, analysis was performed similar to as previously described 62 . In brief, using Fiji/ImageJ software, the raw image was split into three channels as an RGB stack, with the green channel selected for analysis due to its high contrast.…”