Androgens can protect neurones from injury, but androgen neuroprotection is not well characterised in terms of either specificity or mechanism. Here, 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 presence of pyknotic nuclei. According to these criteria, β-amyloid, staurosporine, and Apoptosis Activator II induced cell death involving apoptosis, while hydrogen peroxide (H 2 O 2 ), 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 H 2 O 2 and iron. Similarly, a supra-physiological concentration of oestrogen reduced cell death induced by H 2 O 2 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.

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