Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration

Abstract

Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination. Currently, the cause of MS is unknown. Experimental autoimmune encephalomyelitis (EAE) is the most common mouse model of MS. Treatments with the sex hormones, estrogens and androgens, are capable of offering disease protection during EAE and are currently being used in clinical trials of MS. Beyond endogenous estrogens and androgens, treatments with selective estrogen receptor modulators (SERMs) for estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) are also capable of providing disease protection. This protection includes, but is not limited to, prevention of clinical disease, reduction of CNS inflammation, protection against demyelination, and protection against axonal loss. In EAE, current efforts are focused on using conditional cell specific knockouts of sex hormone receptors to identify the in vivo targets of these estrogens and androgens as well as downstream molecules responsible for disease protection.

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

“…Therefore, we hypothesize that the relatively modest effect on localized GM sparing using VBM may be due to a lack of direct neuroprotective effects of natalizumab. Estrogens, in contrast, have been shown to be neuroprotective in a variety of neurologic disease models (Bode et al., 2008; Engler‐Chiurazzi, Brown, Povroznik, & Simpkins, 2017; Spence & Voskuhl, 2012; Suzuki, Brown, & Wise, 2009), including estriol treatment on cognitive electrophysiologic and neuropathologic outcomes in the MS model (Ziehn, Avedisian, Dervin, O'Dell, & Voskuhl, 2012). …”

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

“…Furthermore, patients in the estriol group without enhancing lesions had less cortical grey matter atrophy than did those in the placebo group, suggesting a direct neuroprotective eff ect independent from antiinfl ammatory eff ects, which is consistent with preclinical studies. 6 Cortical grey matter atrophy on brain MRI has been associated with cognitive dysfunction in patients with multiple sclerosis. 34,35 In addition, oestrogen treatment improves cognitive dysfunction in women without multiple sclerosis who have had ovariectomy, 36 and oestrogen treatment of ovariectomised animals increases dendritic spines and synapses in cerebral grey matter.…”

“…5 Whether estriol treatment could be used in men with multiple sclerosis is unknown. Estriol treatment was protective in male mice in preclinical studies, 6 so it could also be effi cacious in men. However, because estriol treatment in men does not have the history of widespread use that treatment in women has, early phase safety studies are needed before its effi cacy in men with multiple sclerosis can be addressed.…”

“…In addition, further studies are needed to investigate estriol for progressive multiple sclerosis given the neuroprotective eff ects of oestrogens, 6 and our promising exploratory fi ndings of sparing grey matter atrophy and improving cognition. Finally, because estriol is a simple biological molecule, it would be less expensive than many treatments 42 and more accessible to economically disadvantaged patients throughout the world.…”

“…Preclinical studies of multiple sclerosis showed that estriol treatment has both anti-infl ammatory and neuroprotective properties, mediated through binding to oestrogen receptors expressed in the immune system and the CNS. 6 In a small phase 2, single-arm, crossover clinical trial 7 of estriol treatment for ten women with multiple sclerosis, monthly brain MRI showed signifi cant reductions in gadolinium-enhancing lesions during 6 months of treatment compared with 6 months before treatment. Peripheral blood mononuclear cells had signifi cantly increased expression of interleukin 5 and interleukin 10 and decreased concentrations of tumour necrosis factor (TNF) α and matrix metalloproteinase 9.…”