Oestrogen receptor β ligand: a novel treatment to enhance endogenous functional remyelination

Abstract

Demyelinating diseases, such as multiple sclerosis, are characterized by inflammatory demyelination and neurodegeneration of the central nervous system. Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future therapy of multiple sclerosis. Oestrogens and oestrogen receptor ligands are promising treatments to prevent multiple sclerosis-induced neurodegeneration. In the present study we investigated the capacity of oestrogen receptor β ligand treatment to affect callosal axon demyelination and stimulate endogenous myelination in chronic experimental autoimmune encephalomyelitis using electrophysiology, electron microscopy, immunohistochemistry and tract-tracing methods. Oestrogen receptor β ligand treatment of experimental autoimmune encephalomyelitis mice prevented both histopathological and functional abnormalities of callosal axons despite the presence of inflammation. Specifically, there were fewer demyelinated, damaged axons and more myelinated axons with intact nodes of Ranvier in oestrogen receptor β ligand-treated mice. In addition, oestrogen receptor β ligand treatment caused an increase in mature oligodendrocyte numbers, a significant increase in myelin sheath thickness and axon transport. Functional analysis of callosal axon conduction showed a significant improvement in compound action potential amplitudes, latency and in axon refractoriness. These findings show a direct neuroprotective effect of oestrogen receptor β ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis.

Oral contraceptive use and clinical outcomes in patients with multiple sclerosis

“…Current immunologic treatments for RR-MS are known to have a modest effect in preventing accumulation of disability [22]. While safety concerns associated with long-term therapeutic use of sex hormones should be considered [5] our results support a potential benefice of such compounds or their derivatives in combination with currently available immunomodulatory agents for the disease [23]. Overall, our results and previous work suggest that MS women considering the use of OC should not base their decision on potential deleterious effects on their clinical course.…”

“…This interpretation is supported by experimental and clinical data indicating that sex hormones may have protective effects on brain damage and repair mechanisms in these patients [3][4][5]. All oestrogens are not exactly alike [5,23]. Importantly and unlike 17β-oestradiol, the common oestrogen found in pills ethynil oestradiol [24,25] and progesterone [26] reduce the clinical severity of EAE when given after the onset of disease signs.…”

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

“…While the protective effect of estriol treatment on MS appears to be mediated in part by anti‐inflammatory mechanisms (Gold et al., 2009; Soldan, Alvarez Retuerto, Sicotte, & Voskuhl, 2003; Voskuhl & Gold, 2012), this is not mutually exclusive of direct neuroprotective effects, as these have been shown in the MS model (Crawford et al., 2010; Kim et al., 2018; MacKenzie‐Graham et al., 2012; Spence et al., 2011). Together, preclinical data in EAE have shown that estriol is acting to decrease microglial activation, induce remyelination, and increase synaptic plasticity (Kim et al., 2018; Ziehn et al., 2012).…”

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis

“…'s laboratories (8)] was dissolved in 10% ethanol + 90% (vol/vol) Miglyol 812N (vehicle; Sasol) and administered s.c. daily at 5 mg/kg body weight. Control groups received (s.c.) either 0.04 mg/kg/d 17β-estradiol (E2) or 8 mg/kg/48 h DPN (4,10). Treatment was initiated at EAE postinduction day 0 (preEAE) or day 21 (post/peakEAE) and continued until day 40.…”

“…Our recent work has demonstrated promising neuroprotective effects of the estrogen receptor (ER) β agonist 2,3-bis(4-hydroxyphenyl)propionitrile (DPN) (4,5). Although DPN, acting through ERβ, has a desirable palliative effect in EAE, it possesses only 70-fold binding selectivity for ERβ over ERα and lacks anti-inflammatory effects (6,7).…”