Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice

Demyelination and neurodegeneration is a major contributor in the progression of disability in multiple sclerosis (MS). Thus, the development of therapies that are neuroprotective has elicited considerable interests. Estrogens and estrogen receptor (ER) ligand treatments are promising treatments to prevent MS-induced neurodegeneration and a multicenter phase II clinical trial of estriol as a beneficial therapy in MS is underway. Here, we discuss studies performed in our laboratory that examined the effects of ER ligands in the inflammatory/demyelinating disorder experimental autoimmune encephalomyelitis (EAE), a model of MS. Administration of estriol or 17beta-estradiol reduced clinical severity and this clinical disease improvement was associated with favorable changes in cytokine production. There was a significant decrease of neuronal pathology in gray matter along with myelin and axon preservation in white matter of spinal cords of mice with EAE. In subsequent experiments, we contrasted the results of ERalpha versus ERbeta ligand treatment. While ERalpha ligand treatment was anti-inflammatory, ERbeta ligand treatment was not. ERbeta ligand treatment nevertheless reduced demyelination and preserved axon numbers in white matter and prevented neuronal abnormalities in gray matter. Clinically, ERalpha ligand treatment abrogated the disease at the onset, while ERbeta ligand treatment had no effect at disease onset, but promoted recovery. Thus, unlike ERalpha ligand treatment, ERbeta ligand treatment was protective at the level of the target organ, independent of anti-inflammatory effects in the peripheral immune system. ERbeta ligand treatment should be considered as a potential neuroprotective agent for MS and other neurodegenerative diseases, particularly since breast and uterine cancer are mediated through ERalpha.