Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination

Abstract

Remyelinating therapies seek to promote restoration of function and normal cellular architecture following demyelination in diseases, such as multiple sclerosis (MS). Functional screening for small molecules or novel targets for remyelination is a major hurdle to the identification and development of rational therapeutics for MS. Recent findings and technical advances provide us with a unique opportunity to provide insight into the cell autonomous mechanisms for remyelination and address this unmet need. Upon screening a G-protein-coupled receptor small-molecule library, we report the identification of a cluster of -opioid receptor (KOR) agonists that significantly promotes oligodendrocyte differentiation and myelination. KOR agonists were validated in purified rat oligodendroglial cultures, and the (Ϯ)U-50488 compound proved to be most effective for differentiation. (Ϯ)U-50488 treatment significantly enhances differentiation and myelination in purified oligodendroglial cocultures and greatly accelerates the kinetics of remyelination in vivo after focal demyelination with lysolecithin. The effect of (Ϯ)U-50488 is attenuated by KOR antagonists and completely abolished in KOR-null oligodendroglia. Conditional deletion of KOR in murine oligodendrocyte precursor cells (OPCs) greatly inhibits remyelination after focal demyelination lacking any response to (Ϯ)U-50488 treatment. To determine whether agonism of KOR represents a feasible therapeutic approach, human induced pluripotent stem cell-derived OPCs were treated with (Ϯ)U-50488. Consistent with findings, differentiation of human OPCs into mature oligodendrocytes was significantly enhanced. Together, KOR is a therapeutic target to consider for future remyelination therapy.

Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation

“…A promising complementary approach to the treatment of multiple sclerosis, as well as other demyelinating diseases, therefore, involves the identification of pharmacological agents that directly stimulate the process of remyelination by enhancing the process of OPC differentiation 2,10–13 . Recently, our lab and others have identified multiple drug candidates using high-throughput screening approaches that induce OPC differentiation in vitro and enhance remyelination in vivo in relevant rodent models 14–18 . However, additional potential treatment strategies, as well as a systems biology level of understanding of the mechanisms associated with OPC differentiation and function, are clearly still needed.…”

G Protein-Coupled Receptors in Myelinating Glia

“…Excitingly, high-throughput in vitro screens for small molecules and compounds that promote myelination have uncovered several molecular targets of GPCRs, some which have been further validated in vivo [86-90]. For example, starting with a chemical screen for compounds that affect oligodendrocyte differentiation, the Chan lab identified κ-opiod receptor (KOR) agonists as promoters and KOR antagonists as inhibitors of oligodendrocyte differentiation [90].…”

G Protein-Coupled Receptors in Myelinating Glia

“…As Gpr17 is enriched in white matter plaques of MS patients and in rodent models of MS, antagonism of Gpr17 or other inhibitory GPCRs may indeed be efficacious in future treatment strategies [57,64,66,67]. Additional GPCRs have been implicated in CNS myelin repair including Cxcr4, Gpr30, endothelin receptors, and sphingosine 1-phosphate receptors following demyelination in several rodent models [89,90]. Future work elucidating the molecular mechanisms by which GPCRs control developmental myelination and remyelination in both the CNS and PNS will provide invaluable resources for identifying new therapeutic targets in injury and disease.…”

“…Excitingly, high-throughput in vitro screens for small molecules and compounds that promote myelination have uncovered several molecular targets of GPCRs, some which have been further validated in vivo [86][87][88][89][90]. For example, starting with a chemical screen for compounds that affect oligodendrocyte differentiation, the Chan lab identified κ-opiod receptor (KOR) agonists as promoters and KOR antagonists as inhibitors of oligodendrocyte differentiation [90].…”

“…For example, starting with a chemical screen for compounds that affect oligodendrocyte differentiation, the Chan lab identified κ-opiod receptor (KOR) agonists as promoters and KOR antagonists as inhibitors of oligodendrocyte differentiation [90]. Accordingly, genetic deletion of KOR delays developmental myelination in vivo [90], and pharmacologic activation of this GPCR accelerates repair following demyelination in several rodent models [89,90]. Future work elucidating the molecular mechanisms by which GPCRs control developmental myelination and remyelination in both the CNS and PNS will provide invaluable resources for identifying new therapeutic targets in injury and disease.…”