Androgens modulate neuronal vulnerability to kainate lesion

Testosterone has been shown to have multiple beneficial effects on neuronal viability in developing and adult animals. Most often, testosterone promotes neural health indirectly via enzymatic conversion to estradiol by aromatase. Unclear is whether androgens can directly modulate vulnerability to neuronal insults in adult animals. We investigated this issue by modulating androgen status in rats prior to challenge with the excitotoxin kainate. Adult male rats were maintained in the following conditions: i) gonadectomized (GDX) to deplete endogenous androgens, ii) GDX+replacement with dihydrotestosterone (DHT) the active and non-aromatizable testosterone metabolite, iii) sham-GDX. Animals were then lesioned with kainate and surviving hippocampal neurons quantified. In the CA2/3 and hilar regions of the hippocampus, a modest lesion was observed in sham-GDX animals corresponding to approximately 25% cell loss in comparison to non-lesioned rats. The depletion of endogenous androgens by GDX significantly augmented lesion severity, consistent with the hypothesis that androgens are involved in maintaining cell viability. Importantly, DHT hormone replacement in GDX rats significantly attenuated kainate-induced neuron loss in CA2/3, suggesting direct androgen neuroprotection. These results demonstrate that androgens act as endogenous modulators of neuron viability, a function that may be compromised in aging men as a consequence of normal, age-related androgen depletion.