A neuroactive steroid 5α-androstane-3α,17β-diol regulates androgen receptor level in astrocytes

Optic nerve head (ONH) astrocytes from patients with glaucomatous optic neuropathy exhibit increased production of 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol), a neuroactive metabolite of 5 alpha-dihydrotestosterone (5 alpha-DHT). To determine whether ONH astrocytes are androgen target cells, and whether 3 alpha-diol is capable of regulating astrocyte functions, we studied the response of human ONH astrocytes to 3 alpha-diol compared with 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one (R1881), a synthetic 5 alpha-DHT agonist. In ONH astrocytes, both 3 alpha-diol and R1881 increased protein levels of androgen receptor (AR) and glial fibrillary acidic protein (GFAP), however, only R1881 also increased the AR mRNA level and astrocyte proliferation. Both R1881 and 3 alpha-diol rapidly activate the mitogen-activated protein kinase (MAPK) signaling pathway in ONH astrocytes, as confirmed by phosphorylation of extracellular signal-regulated kinase (ERK). 3 alpha-diol also activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. 3 alpha-diol regulates the increase of AR protein level and the phosphorylation through the PI3K/Akt pathway, whereas R1881 regulates them through the MAPK/ERK pathway. Our findings demonstrate that human ONH astrocytes are androgen target cells and respond to androgens by the rapid activation of cell signaling. The activation of the PI3K/Akt pathway by 3 alpha-diol may regulate various properties of astrocytes, including cell motility and survival, and may play a role in the formation and maintenance of the reactive phenotype of ONH astrocytes in glaucoma.