Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

Abstract

Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

Figure 1. Microglia activation and neural cell loss

Activation of microglia causes the secretion of short-lived diffusible molecules, such as reactive oxygen species (ROS), that produce an oxidative burst that is directly toxic to surrounding cells. In addition, peptides and inflammatory mediators are produced by activated microglia to communicate the ongoing local reaction to the periphery; circulating inflammatory cells are attracted by these molecules to the injured site and further sustain the local inflammatory reaction. Secretion of neurotrophic factors, as well as elimination of noxious material from the extracellular space through phagocytosis are also key features of microglia activation, which have instead beneficial consequences for brain health.

Figure 2. Estrogen anti-inflammatory action

Schematic representation of the mechanism of action of estradiol in microglia proposed by our lab. The cytoplasmic activity of estrogen-activated ERα, including PI3K induction, inhibits the intracellular transport of NF-kB that is induced by inflammatory stimuli, such as LPS; this leads to reduced synthesis of inflammatory mediators and microglia activation.