Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis

Itoh, Noriko; Kim, Roy; Peng, Mavis; DiFilippo, Emma; Johnsonbaugh, Hadley; MacKenzie-Graham, Allan; Voskuhl, Rhonda R.

doi:10.1016/j.jneuroim.2016.09.017

Cited by 34 publications

(18 citation statements)

References 54 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These observations pointed towards the involvement of sex hormones, such as estrogen and estriol in disease regulation (Baker et al, 2004, Bebo et al, 2001, Drew et al, 2003, Itoh et al, 2016, Offner and Polanczyk, 2006). It was further demonstrated that the composition of gut microbiota changes during pregnancy (Koren et al, 2012).…”

Section: Discussionmentioning

confidence: 97%

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Benedek

Zhang

Nguyen

et al. 2017

Journal of Neuroimmunology

View full text Add to dashboard Cite

Sex hormones promote immunoregulatory effects on multiple sclerosis. In the current study we evaluated the composition of the gut microbiota and the mucosal-associated regulatory cells in estrogen or sham treated female mice before and after autoimmune encephalomyelitis (EAE) induction. Treatment with pregnancy levels of estrogen induces changes in the composition and diversity of gut microbiota. Additionally, estrogen prevents EAE-associated changes in the gut microbiota and might promote the enrichment of bacteria that are associated with immune regulation. Our results point to a possible cross-talk between the sex hormones and the gut microbiota which could promote neuroprotection.

show abstract

Section: Discussionmentioning

confidence: 97%

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Benedek

Zhang

Nguyen

et al. 2017

Journal of Neuroimmunology

View full text Add to dashboard Cite

show abstract

“…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). Further, we have shown that treatment with estrogens and estrogen receptor ligands prevented both cortical and cerebellar GM atrophy by MRI, which correlated with preserving axons, neurons, and synapses in EAE (Itoh et al., 2017; Kim et al., 2018; MacKenzie‐Graham et al., 2012). Consistent with this, treatment with estrogens has been associated with neuroprotection in mouse models of ischemic stroke, Alzheimer's disease, Parkinson's disease, and Huntington's disease (Bode et al., 2008; Morissette, Al Sweidi, Callier, & Di Paolo, 2008; Suzuki et al., 2009; Yue et al., 2005).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

Self Cite

View full text Add to dashboard Cite

IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

show abstract

“…In contrast, treatment with selective ER modulators (SERMs) indicated that ERβ was capable of providing protection against neurodegeneration, whereas ERα was anti-inflammatory [40,41]. ERβ ligands have been proposed as the next-generation estriol treatment, given their protective effect across both sexes [42]. It should be noted that the immunomodulatory effects of tamoxifen may be independent of the estrogen-receptor with its immunomodulation mediated through the multidrug resistance gene product, permeability-glycoprotein [43].…”

Section: Estradiol Synthetic Estrogens and Estriolmentioning

confidence: 99%

The Role of Sex Hormones in Multiple Sclerosis

et al. 2018

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.

show abstract

Bedside to bench to bedside research: Estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis

Cited by 34 publications

References 54 publications

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells

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

The Role of Sex Hormones in Multiple Sclerosis

Contact Info

Product

Resources

About