Comparison of the therapeutical effects of dexamethasone (a synthetic glucocorticoid analogue), and G1 (a G-coupled estrogen receptor, GPER agonist) on the EAE-induced neuroinflammation

Abstract

Multiple sclerosis (MS) is a debilitating neurological and autoimmune disease, characterized by inflammation, demielinization, and neurodegeneration. Neuroinflammation is an important finding in MS pathogenesis, contributing for the progression of the disease. Glial cells (microglia and astrocytes) also have a key role in the progression of MS. Systemic corticosteroids, such as dexamethasone, remain the most established and validated treatment options for MS. Despite women are more prone to develop MS, they show clinical improvement when estrogens, in supraphysiologic dosage, is used. However, an important issue regarding their therapeutic application has been the undesirable estrogenic side effects, such as cell proliferation, thought to be mediated primarily through estrogen nuclear receptor alpha (ER±). In addition, very few studies have investigated the estrogen effects on glial and immune cells and little is known about the molecular pathways this hormone interacts with. Taken that, the first aim of this study is to investigate, in vitro, the role of G1, a G-coupled estrogen receptor - GPER - agonist, on the INFg- and IL17-induced inflammatory response in primary cell cultures from neonate C57BL/6 female mice co-cultured with lymphocytes T cell lineage (D1110) and compare them to those from dexamethasone treatment. Second, we aim to verify the functionality of these in vitro findings at the progression of Experimental autoimmune encephalomyelitis (EAE), the experimental model of MS. With this study, we seek to better understand the molecular mechanisms by which estrogen and glucocorticoids modulate neuroinflammation and to provide either new pharmacological tools or to maximize the therapeutical benefits of those already known about using these hormones. (AU)