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.

Fig. 1

Simplified model of estrogen’s actions for disease protection during EAE. (1) Estradiol (E2) and estriol (E3) act on dendritic cells (red) in the periphery to provide protection during EAE [71,108]. (2) Estradiol and ERα ligand act on B-cells (light blue) to provide protection during EAE [11]. (3) ERα ligand acts on T-cells (purple) to prevent EAE [67]. (4) Estradiol, estriol, and ERα ligand prevent inflammation into the CNS during EAE [7,59,66,92,141]. (5) ERα and ERβ act on the astrocytes (dark blue) to promote disease protection [122,134]. (6) ERβ acts on dendritic cells (red) in the CNS to provide protection during EAE [33]. (7) ERβ acts on microglia to provide protection during EAE [122]. (8) Estradiol, estriol, ERα and ERβ ligand treatment during EAE prevent axonal loss [7,59,92,141]. (9) ERβ ligand promotes remyelination of axons during EAE [23]. (10) Estradiol, estriol, ERα and ERβ ligand prevent demyelination during EAE [7,59,92,141].