Testosterone‐mediated neuroprotection through the androgen receptor in human primary neurons

Abstract

Estrogen is an active neuroprotectant and is presently investigated as a potential therapy against Alzheimer's disease for women. To determine if male hormones could also be neuroprotective, we investigated the effect of testosterone, methyltestosterone, and epitestosterone at physiological concentrations on primary cultures of human neurons induced to undergo apoptosis by serum deprivation. Serum deprivation signi®cantly induces neuronal apoptosis in a protracted fashion. As expected, physiological concentrations of 17-bestradiol and transcriptionally inactive 17-a-estradiol protect neurons against apoptosis. Similar to 17-b-estradiol, physiological concentrations of testosterone are also neuroprotective. Androgen receptors are present at 8^2 fmol/mg protein in the neuron cultures. The non-aromatizable androgen, mibolerone, is also neuroprotective and aromatase inhibitor, 4-androsten-4-OL-3,17-dione, does not prevent testosteronemediated neuroprotection. In contrast, anti-androgen,¯utamide, eliminates testosterone-mediated neuroprotection. Testosterone analog, methyltestosterone, showed androgen receptordependent neuroprotection that was delayed in time indicating that a metabolite may be the active agent. The endogenous anti-androgen, epitestosterone, also showed a slight neuroprotective effect but not through the androgen receptor. These results indicate that androgens induce neuroprotection directly through the androgen receptor. These data suggest that androgens may also be of therapeutic value against Alzheimer's disease in aging males.

Non-genomic actions of androgens

“…Dihydrotestosterone has been found to regulate cellular growth, differentiation, survival, or death through both genomic and non-genomic signaling pathways [160]. Androgens, including T and DHT, can protect neurons from various insults in culture, including kainic acid toxicity [161], β-amyloid toxicity [162; 163] and serum deprivation [164], and have been shown to rapidly activate the cytoprotection-associated ERK/MAPK pathway [161; 163]. The receptor mediating these protective effects is thought to be AR due to the fact that AR antagonists block the neuroprotective effects [163; 164].…”

Estrogen and Androgen Protection of Human Neurons against Intracellular Amyloid 1-42 Toxicity through Heat Shock Protein 70

“…Testosterone protects primary human neurons against serum deprivation (Hammond et al, 2001), cultured rat hippocampal neurons against extracellular A␤ toxicity (Pike, 2001), rat neurons against heat shock-mediated hyperphosphorylation of tau by modulating glycogen synthase kinase 3␤ activation (Papasozomenos and Shanavas, 2002), cerebellar granule neurons against oxidative stress (Ahlbom et al, 1999(Ahlbom et al, , 2001, and rat hippocampal neurons against kainic acid-induced toxicity (Ramsden et al, 2003); testosterone also promotes neuritic extension in pheochromocytoma 12 cells (Lustig et al, 1994). Testosterone can protect through the androgen receptor (AR) rather than through aromatization into estrogen (Ahlbom et al, 2001;Hammond et al, 2001;Ramsden et al, 2003).…”

Elevated Testosterone Induces Apoptosis in Neuronal Cells

“…The gonadal steroid hormones are required for reproductive function, but androgens also affect areas of the brain that are not primarily involved in reproduction such as the hippocampus (5), preoptic area, amygdala, and medial hypothalamic area (6). At physiological levels, androgens are involved in neuronal differentiation, neuroprotection, neuronal survival and development (7)(8)(9). These responses occur slowly (over hours) and are mediated through the intracellular androgen receptor.…”