Future directions for using estrogen receptor agonists in the treatment of acute and chronic spinal cord injury

All synthetic and natural estrogen receptor agonists, including the most potent physiological molecule estrogen or estradiol (E2), work typically via activation of nuclear estro-gen receptor alpha (ERα) and estrogen receptor beta (ERβ). Both ERα and ERβ modulate the expression of a variety of genes in the cells. Neurons and glial cells express ERα and ERβ. Many studies so far from our and other laboratories have firmly established the mode of actions that ERα and ERβ agonists are very promising anti-inflammatory and neuroprotective agents in the treatment of neurodegenera-tive diseases and injuries including spinal cord injury (SCI) (Chakrabarti et al., 2014a). There are selective ERα agonists and also selective ERβ agonists but E2 works via both ERα and ERβ to mediate its anti-inflammatory and neuroprotec-tive effects. Our studies show that E2 is a better therapeutic agent than a selective ERα agonist such as 1,3,5-tris (4-hy-droxyphenyl)-4-propyl-1H-pyrazole and a selective ERβ ag-onist such as 2,3-bis (4-hydroxyphenyl) propionitrile or Way 200070 to provide functional neuroprotection in cell culture models of SCI (Das et al, 2011; Chakrabarti et al., 2014b). We have also recently reported that E2 even at a low dose provides highly significant therapeutic efficacy for amelioration of neurodegeneration and recovery of locomotor function in animal models of acute SCI (Samantaray et al., 2016a) and chronic SCI (Samantaray et al., 2016b). Future studies for using E2 in the treatment of SCI in animal models need to be focused on optimal enhancement of its multi-active therapeutic effects at a physiologically relevant further low dose, may be, in combination with another therapeutic agent. Although there are three main naturally occurring es-trogens such as estrone (E1), E2, and estriol (E3), E2 is the most prevalent and highly potent steroidal sex hormone in females. Being the primary sex hormone in females, E2 plays not only the vital roles in remodeling and regulation of the reproductive system but it also contributes to cognitive function in the central nervous system (CNS). When compared with females, E2 level is significantly low in males. However, E2 even at a very low level has important roles in maintaining overall health in males. Because E2 can easily pass through the blood-brain barrier and diffuse across the cell membrane, it is readily available to bind to and activate the nuclear ERα and ERβ to modulate expression of many target genes for anti-inflammatory and neuroprotective effects in the CNS cells following a CNS injury such …