Estrogen Receptors
The estrogen receptors α (ERα, NR3A1) and β (ERβ, NR3A2) are both present in rodent brain, although in different locations (Warner & Gustafsson, 2015), as are their classical steroid hormone agonists (Li & Gibbs, 2019) and oxysterol modulators (Griffiths et al., 2019a; Meljon et al., 2019). ERβ has a role in the migration of cortical neurons in the developing brain, where it is detectable at E12.5 (Wang, Andersson, Warner & Gustafsson, 2003), and in adult in the maintenance of serotonergic neurons in the dorsal raphe nucleus, involved in fear, anxiety and depression (Suzuki et al., 2013). ERα is expressed in spinal cord motor neurons where it has a role in protecting neurons against cytokine toxicity (Das, Smith, Gibson, Varma, Ray & Banik, 2011). Both ERα and ERβ are protective against EAE, a mouse model of multiple sclerosis (Spence et al., 2013). The protective effect of ERα is through astrocytes but that of ERβ through microglia (Wu, Tan, Dai, Krishnan, Warner & Gustafsson, 2013). Microglia are the macrophages of the brain, and when activated can damage healthy neurons in the region of infection. ERβ selective agonists dampen the activation of microglia and reduce the proinflammatory potential of invading T-cells (Warner & Gustafsson, 2015; Wu, Tan, Dai, Krishnan, Warner & Gustafsson, 2013).
Besides the ER ligands based on the estradiol skeleton, oxysterols can also act as ligands to both ERα and ERβ (DuSell, Umetani, Shaul, Mangelsdorf & McDonnell, 2008; Umetani et al., 2007). Umetani et al in 2007 and DuSell et al in 2008 both identified 27-HC, presumably (25R)26-HC, as a selective estrogen receptor modulator (SERM) (DuSell, Umetani, Shaul, Mangelsdorf & McDonnell, 2008; Umetani et al., 2007). SERMs are ER ligands whose relative agonist/antagonist activities vary in a cell- and promotor-dependent manner (Wardell, Nelson & McDonnell, 2014). Selectivity is based on the ability of ligands to induce alterations in the ER structure leading to differential recruitment of co-activators and co-repressors. (25R)26-HC induces conformational changes in both ERα and ERβ. Interestingly, (25R)26-HC is a competitive antagonist of ER action in the vasculature (Umetani et al., 2007) but has ER agonist activity in breast cancer cells (DuSell, Umetani, Shaul, Mangelsdorf & McDonnell, 2008). Although most studies of (25R)26-HC and ER have been made in the context of breast cancer (Nelson et al., 2013; Wu et al., 2013) the possibility exists that (25R)26-HC may act as a SERM in the CNS.
In mouse and human brain levels of (25R)26-HC are low (~ 1 ng/mg) (Griffiths et al., 2019a; Heverin et al., 2004; Meljon et al., 2019), but are elevated in the Cyp7b1 -/- mouse (~ 5 ng/mL) (Meljon et al., 2019), and presumably in sufferers of SPG5 where CYP7B1 is deficient and one route of (25R)26-HC metabolism blocked (Figure 3). A raised content of (25R)26-HC in SPG5 brain has not been considered in the context of (25R)26-HC as a SERM, but the role of ERα in the protection of spinal cord motor neurons may be relevant with (25R)26-HC acting as an ERα antagonist in SPG5 where motor neurons are lost. 25-Hydroxycholesterol (25-HC) is also a SERM and is also elevated in Cyp7b1 -/- mouse brain (Meljon et al., 2019; Simigdala et al., 2016).