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

Kelly F Paton,Bronwyn M Kivell,Dan Luo,Nikki Templeton,Thomas E Prisinzano,Lisa Denny,Katharina Robichon,Anne C La Flamme,Afnan Al Abadey

doi:10.3389/fneur.2021.782190

Abstract

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.

Highlights

Multiple sclerosis (MS) is a devastating autoimmune disease characterized by the infiltration of autoreactive CD4 T cells in the central nervous system (CNS) leading to damage of the myelin sheaths surrounding axons, resulting in demyelination
EOM SalB is an analog of Salvinorin A with alteration at the carbon-2 position, which is structurally distinct from the prototypical kappa opioid receptor (KOR) agonist U50,488 (Figure 1A)
Using U50,488 as the reference ligand, the results show that EOM SalB was more potent than the parent compound Salvinorin A and U50,488 in both assays (Figures 1B,C, Table 1)

Summary

Introduction

Multiple sclerosis (MS) is a devastating autoimmune disease characterized by the infiltration of autoreactive CD4 T cells in the central nervous system (CNS) leading to damage of the myelin sheaths surrounding axons, resulting in demyelination. MS can be broadly divided into three different subtypes: relapsingremitting, primary progressive and secondary progressive. There is no cure for MS, with current disease-modifying treatments targeting the immune system to reduce damage to the myelin sheath formed by oligodendrocytes. The current treatments have limitations in preventing the progression of disability and are more successful at treating the relapsingremitting forms of the disease [3]. There is a current need to develop therapeutics that can induce remyelination, which could greatly benefit patients suffering from progressive forms of MS

Objectives

Methods

Results

Conclusion