Estrogen receptors (ERs) have long been implicated in the etiology of multiple sclerosis, but no clear molecular mechanisms have linked ERs to the disease's pathology. Now Saijo et al. (2011) provide evidence that ERβ activates a transrepression pathway that suppresses inflammation and inhibits progression of pathology in a mouse model of multiple sclerosis.
"Consequently, treatment with ERb-specific ligands conferred neuroprotection against experimentally induced autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis (MS) (Saijo et al., 2011). Thus, the progression of MS, and possibly other autoimmune disorders of the brain, could potentially be linked to a dysregulated ERb transrepression pathway (Gosselin and Rivest, 2011). 3.2. "
[Show abstract][Hide abstract] ABSTRACT: Inflammation is a protective response of organisms to pathogens, irritation or injury. Primary inflammatory sensors activate an array of signaling pathways that ultimately converge upon a few transcription factors such as AP1, NFκB and STATs that in turn stimulate expression of inflammatory genes to ultimately eradicate infection and repair the damage. A disturbed balance between activation and inhibition of inflammatory pathways can set the stage for chronic inflammation which is increasingly recognized as a key pathogenic component of autoimmune, metabolic, cardiovascular and neurodegenerative disorders. Nuclear Receptors (NRs) are a large family of transcription factors many of which are known for their potent anti-inflammatory actions. Activated by small lipophilic ligands, NRs interact with a wide range of transcription factors, cofactors and chromatin-modifying enzymes, assembling numerous cell- and tissue-specific DNA-protein transcriptional regulatory complexes with diverse activities. Here we discuss established and emerging roles and mechanisms by which NRs and, in particular, the glucocorticoid receptor (GR) repress genes encoding cytokines, chemokines and other pro-inflammatory mediators.
[Show abstract][Hide abstract] ABSTRACT: Gray matter (GM) atrophy is common in multiple sclerosis (MS), as is cognitive dysfunction. Understanding the exact relationship between atrophy and cognition requires further investigation. The aim of this study was to investigate the relationship between subcortical GM atrophy and cognition in early relapsing onset MS.
Structural MRI and neuropsychological evaluations were performed in 120 patients (80 women) and 50 controls (30 women), part of an early inception cohort, 6 years postdiagnosis. Deep GM volumes were segmented automatically. Cognition was assessed in 7 domains. Stepwise linear regression was used to predict average cognition in the patient group.
Most deep GM volumes were reduced in patients, with larger effects on average in men (-11%) than in women (-6.3%). Only the bilateral hippocampus, amygdala, and right nucleus accumbens in men, and right hippocampus and nucleus accumbens, bilateral amygdala, and putamen in women, showed no atrophy compared to controls. All cognitive domains except visuospatial memory were affected in men; none were significantly affected in women. In the MS group, average cognition was best predicted by thalamic volume, sex, and education (adjusted R(2) = 0.31), while lesion volume was not a significant predictor in the model.
Six years postdiagnosis, almost all subcortical structures were affected by MS, especially in men. Cognition was most severely affected in male patients. Thalamic volume, sex, and education best predicted average cognition. These results underline the relevance of specific subcortical structures to cognition, as well as the relevance of (sex-specific) atrophy in MS.
[Show abstract][Hide abstract] ABSTRACT: Gonadal steroids are critical regulators of physiology, yet we approach physiology and science with the simplest perspective/model, the male one. Female models of whole animal physiology are complex to study and, therefore, are often not used in research. Estrogens are one of the sex hormones that we know are important for both men and women. Estrogens regulate key features of metabolism such as food intake, body weight, glucose homeostasis/insulin sensitivity, body fat distribution, lipolysis/lipogenesis, inflammation, locomotor activity, energy expenditure, reproduction, and cognition. Furthermore, estrogens have multiple sites of action including some unexpected ones, which was demonstrated elegantly through a series of papers this year.
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