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Activation of a Membrane-Associated Androgen Receptor Promotes Cell Death in Primary Cortical Astrocytes

Department of Pharmacology and Neuroscience, The Institute for Aging and Alzheimer’s Disease Research, and The Center FOR HER (Focused On Resources for HER Health Education Research), University of North Texas Health Science Center, Fort Worth, Texas 76107

Address all correspondence and requests for reprints to: Meharvan Singh, Ph.D., Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3400 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699. E-mail: msingh{at}hsc.unt.edu.

In the central nervous system, androgens can exert either protective or damage-promoting effects. For example, testosterone protects neurons against ß-amyloid toxicity, whereas in other studies, testosterone exacerbated stroke-induced lesion size. The mechanism underlying this duality of androgens is still unclear. Recently, our laboratory reported that androgens elicit opposite effects on the ERK/MAPK and Akt signaling pathways, depending on whether a membrane androgen receptor (AR) or intracellular AR was activated. By extension, we hypothesized that androgens may affect cell viability differently depending on which receptor is activated. Here, we found that dihydrotestosterone (DHT) protected primary cortical astrocytes from the metabolic and oxidative insult associated with iodoacetic acid-induced toxicity, whereas DHT-BSA, a cell impermeable analog of DHT that preferentially targets the membrane AR, suppressed Akt signaling, increased caspase 3/7 activity, and enhanced iodoacetic acid-induced cell death. Interestingly, DHT-BSA also blocked the protective effects of DHT and estradiol. Collectively, these data support the existence of two, potentially competing, pathways for androgens in a given cell or tissue that may provide insight into the controversy of whether androgen therapy is beneficial or detrimental.