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O.A. Agapova, P.E. Malone, M.R. Hernandez; The Neurosteroid 5–Androstane–3,17ß–diol (3–diol) Activates IP3K/Akt Pathway in Optic Nerve Head Astrocytes . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3798.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the response of human optic nerve head (ONH) astrocytes to the neurosteroid 5α–androstane–3α,17ß–diol (3α–diol). 3α–diol is the product of 5α–dihydrotestosterone conversion by AKR1C2, an androgen metabolizing enzyme which is over expressed in ONH astrocytes from glaucoma patients. Methods: ONH astrocytes from normal donors were treated with 3α–diol and R1881, a synthetic non–metabolizable androgen. Western blot and immunoprecipitation were used to detect GFAP and androgen receptor (AR) protein levels and phosphorylation, and quantitative real time RT–PCR (Q–PCR) was used to analyze mRNA expression. Involvement of the signal transduction pathways regarding the androgen response was determined using specific inhibitors of MEK1 (UO126), PI3K (LY 294002), Src (PP2) and PKC (Gö6850). Results: ONH astrocytes exposed to R1881 and 3α–diol increased AR and GFAP protein levels but not mRNA levels after 3–24 h treatment. R1881 and 3α–diol stimulate phosphorylation of ERK1/2 after treatment for 5–30 min, but not p38 phosphorylation or Src and Ras activation. 3α–diol induced a specific Akt phosphorylation after 10–30 min. Inhibition of ERK1/2 phosphorylation blocked AR protein increase in response to R1881 and 3α–diol, whereas LY294002, a specific inhibitor of PI3K, blocked AR increase induced by 3α–diol, but not by R1881. Conclusions: ONH astrocytes respond to androgen stimulation by increasing protein levels of AR, a central mediator of androgen action, and GFAP, a marker of reactive astrocytes. 3α–diol, but not R1881, activates the PI3K/Akt signaling pathway in astrocytes. 3α–diol, acting via the PI3K/Akt pathway, may induce and maintain the reactive phenotype in glaucomatous optic neuropathy.
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