Androgens Selectively Protect Against Apoptosis in Hippocampal Neurones

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Abstract
Androgens can protect neurones from injury, although androgen neuroprotection is not well characterised in terms of either specificity or mechanism. In the present study, we compared the ability of androgens to protect neurones against a panel of insults, empirically determined to induce cell death by apoptotic or non‐apoptotic mechanisms. Three criteria defining but not inclusive of apoptosis are: protection by caspase inhibition, protection by protein synthesis inhibition and the presence of pyknotic nuclei. According to these criteria, β‐amyloid, staurosporine, and Apoptosis Activator II induced cell death involving apoptosis, whereas hydrogen peroxide (H2O2), iron, calcium ionophore and 3‐nitropropionic acid induced cell death featuring non‐apoptotic characteristics. Pretreatment of hippocampal neurones with testosterone or dihydrotestosterone attenuated cell death induced by β‐amyloid, staurosporine and Apoptosis Activator II, but none of the other insults. The anti‐oxidant Trolox did not reduce cell death induced by β‐amyloid, staurosporine and Apoptosis Activator II, but did protect against H2O2 and iron. Similarly, a supra‐physiological concentration of oestrogen reduced cell death induced by H2O2 and iron, an effect not observed with androgens. We also show that activation of oestrogen pathways was not necessary for androgen neuroprotection. These data suggest that androgens directly activate a neuroprotective mechanism specific to inhibition of cell death involving apoptosis. Determining the specificity of androgen neuroprotection may enable the development of androgen compounds for the treatment of neurodegenerative disorders.