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

Abstract

ObjectivesMultiple 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.MethodsUsing 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.ResultsFingolimod 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.ConclusionThis study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine–fingolimod combination providing enhanced benefits.

Identification and In Vivo Evaluation of Myelination Agent PIPE-3297, a Selective Kappa Opioid Receptor Agonist Devoid of β-Arrestin-2 Recruitment Efficacy

“…Asimadoline and quinoxalines are believed to exert their effects via peripheral mechanisms, as they are proposed to not cross the blood–brain barrier, although no supportive pharmacokinetic data have been provided. The clinically approved morphinan-based KOR agonist nalfurafine has been studied extensively in the context of remyelination and EAE. , Nalfurafine, a full activator of β-arrestin signaling in vitro, has been reported to exhibit affinity-dominant G-protein bias, ,− but the functional selectivity appears to be highly context-dependent as others have reported nalfurafine to be unbiased or biased toward β-arrestin signaling. , The highly potent nalfurafine exhibited efficacy in therapeutic EAE at daily doses as low 300 ng/kg/day dosed intraperitonally. In a head-to-head experiment, nalfurafine (10 μg/kg/day i.p.)…”