Androgens Selectively Protect Against Apoptosis in Hippocampal Neurones

Abstract

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.

The Effect of Testosterone on the Formation of Brain Structures

“…[Nguyen et al, 2010]. A similar neuroprotective effect is also observed after estradiol application [McCarthy, 2008].…”

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

“…Cell culture models of neural injury have demonstrated testosterone protection against serum deprivation [102,155], A toxicity [156][157][158], and oxidative damage [159]. Testosterone neuroprotection against serum deprivation-induced apoptosis requires activation of an androgen receptor (AR) dependent mechanism [102,155].…”

“…Protects against neuronal cell death in vitro [102,[155][156][157][158][159], attenuates neuron loss from excitotoxic lesion [153,154], activates kinase Rsk to inactivate the pro-apoptotic protein Bad [157] Reduce A in vivo [31; 162, 164-165, 168], possibly by activating neprilysin [167] Prevents tau hyper-phosphorylation [171][172][173] by inhibiting GSK signaling [171], regulate calpain-mediated proteolytic tau cleavage [174] ters affecting HT efficacy will be optimized, including age of HT initiation as well as the formulation, regimen, and delivery of HT. Results from both epidemiological studies and previous clinical trials suggest that duration or hormone therapy and age at initiation may be two of the most important factors to consider in regards to the most effect treatment.…”

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

“…neurosteroid | exercise-induced neurogenesis | low intensity exercise | de novo synthesis | paracrine G onadal hormones enhance neuronal plasticity, including adult hippocampal neurogenesis (AHN), which occurs in the dentate gyrus throughout life in mammals (1, 2)-as well as having neuroprotective effects (3)(4)(5)(6). In particular, the hippocampus is known to be a target of androgen actions (5,7,8).…”