Abstract
Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.
Highlights
In EAE, it possesses only 70-fold binding selectivity for ERβ over ERα and lacks anti-inflammatory effects [6, 7]
Our results indicate that indazole chloride (Ind-Cl) is effective in functionally ameliorating disease even when treatment is initiated at peak experimental autoimmune encephalomyelitis clinical disease
Synthetic ERβ-specific ligands based on a halogensubstituted phenyl-2H-indazole core [8], potently inhibit transcriptional activation of inflammatory response genes in microglia and astrocytes [7]
Summary
In EAE, it possesses only 70-fold binding selectivity for ERβ over ERα and lacks anti-inflammatory effects [6, 7]. The structurally unique ERβ ligand indazole chloride (Ind-Cl), based on a halogen-substituted phenyl-2H-indazole core, is a preclinical development candidate with a strong dossier, including in vitro pharmacology using rodent and human cells, selectivity and potency data, promising absorption-distribution-metabolismexcretion findings, and pharmacokinetic profiling that includes confirmation of brain penetrability (mouse brain/plasma: ∼1.0) [7, 8]. It is a highly ERβ-selective (>100-fold) small molecule agonist that is administered s.c. and can be developed for oral administration [7]. A treatment that stimulates endogenous OPCs to differentiate and remyelinate axons would reduce axon degeneration and restore neuronal function
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